Compounds for treating spinal muscular atrophy

ABSTRACT

Provided herein are compounds, compositions thereof and uses therewith for treating spinal muscular atrophy.

CROSS-REFERENCE

This application is a divisional of U.S. application Ser. No.15/248,052, filed Aug. 26, 2016, currently allowed, which is acontinuation of U.S. application Ser. No. 14/377,531, filed Aug. 8,2014, issued as U.S. Pat. No. 9,586,955 on Mar. 7, 2017, which is a U.S.national stage application of International Patent Application No.PCT/US2013/025292, filed Feb. 8, 2013, which claims the benefit ofpriority to U.S. Provisional Application Ser. No. 61/597,523, filed Feb.10, 2012, the entire contents of which are incorporated herein byreference in its entirety and for all purposes.

The technology described herein has not been made with U.S. Governmentsupport.

STATEMENT ON JOINT RESEARCH AGREEMENT

The subject matter disclosed was developed and the claimed invention wasmade by, or on behalf of, one or more parties to a joint researchagreement that was in effect on or before the effective filing date ofthe claimed invention;

the claimed invention was made as a result of activities undertakenwithin the scope of the joint research agreement; and

the application for patent for the claimed invention discloses or isamended to disclose the names of the parties to the joint researchagreement. The parties of the joint research agreement are PTCTherapeutics, Inc. and F. Hoffmann-La Roche AG.

INTRODUCTION

Provided herein are compounds, compositions thereof and uses therewithfor treating Spinal Muscular Atrophy.

BACKGROUND

Spinal muscular atrophy (SMA), in its broadest sense, describes acollection of inherited and acquired central nervous system (CNS)diseases characterized by progressive motor neuron loss in the spinalcord and brainstem causing muscle weakness and muscle atrophy. The mostcommon form of SMA is caused by mutations in the Survival Motor Neuron(SMN) gene and manifests over a wide range of severity affecting infantsthrough adults (Crawford and Pardo, Neurobiol. Dis., 1996, 3:97).

Infantile SMA is the most severe form of this neurodegenerativedisorder. Symptoms include muscle weakness, poor muscle tone, weak cry,limpness or a tendency to flop, difficulty sucking or swallowing,accumulation of secretions in the lungs or throat, feeding difficulties,and increased susceptibility to respiratory tract infections. The legstend to be weaker than the arms and developmental milestones, such aslifting the head or sitting up, cannot be reached. In general, theearlier the symptoms appear, the shorter the lifespan. As the motorneuron cells deteriorate, symptoms appear shortly afterward. The severeforms of the disease are fatal and all forms have no known cure. Thecourse of SMA is directly related to the rate of motor neuron celldeterioration and the resulting severity of weakness. Infants with asevere form of SMA frequently succumb to respiratory disease due toweakness in the muscles that support breathing. Children with milderforms of SMA live much longer, although they may need extensive medicalsupport, especially those at the more severe end of the spectrum. Theclinical spectrum of SMA disorders has been divided into the followingfive groups.

(a) Type 0 SMA (In Utero SMA) is the most severe form of the disease andbegins before birth. Usually, the first symptom of Type 0 SMA is reducedmovement of the fetus that can first be observed between 30 and 36 weeksof pregnancy. After birth, these newborns have little movement and havedifficulties with swallowing and breathing.

(b) Type 1 SMA (Infantile SMA or Werdnig-Hoffmann disease) typicallypresents symptoms between 0 and 6 months. This form of SMA is also verysevere. Patients never achieve the ability to sit, and death usuallyoccurs within the first 2 years without ventilatory support.

(c) Type 2 SMA (Intermediate SMA) has an age of onset at 7-18 months.Patients achieve the ability to sit unsupported, but never stand or walkunaided. Prognosis in this group is largely dependent on the degree ofrespiratory involvement.

(d) Type 3 SMA (Juvenile SMA or Kugelberg-Welander disease) is generallydiagnosed after 18 months. Type 3 SMA individuals are able to walkindependently at some point during their disease course but often becomewheelchair-bound during youth or adulthood.

(e) Type 4 SMA (Adult onset SMA). Weakness usually begins in lateadolescence in the tongue, hands, or feet, then progresses to otherareas of the body. The course of adult SMA is much slower and has littleor no impact on life expectancy.

The SMN gene has been mapped by linkage analysis to a complex region inchromosome 5q. In humans, this region contains an approximately 500thousand base pairs (kb) inverted duplication resulting in two nearlyidentical copies of the SMN gene. SMA is caused by an inactivatingmutation or deletion of the telomeric copy of the gene (SMN1) in bothchromosomes, resulting in the loss of SMN1 gene function. However, allpatients retain the centromeric copy of the gene (SMN2), and the copynumber of the SMN2 gene in SMA patients generally correlates inverselywith the disease severity; i.e., patients with less severe SMA have morecopies of SMN2. Nevertheless, SMN2 is unable to compensate completelyfor the loss of SMN1 function due to alternative splicing of exon 7caused by a translationally silent C to T mutation in exon 7. As aresult, the majority of transcripts produced from SMN2 lack exon 7 (SMN2Δ7), and encode a truncated Smn protein that has an impaired functionand is rapidly degraded.

The Smn protein is thought to play a role in RNA processing andmetabolism, having a well characterized function of mediating theassembly of a specific class of RNA-protein complexes termed snRNPs. Smnmay have other functions in motor neurons, however its role inpreventing the selective degeneration of motor neurons is not wellestablished.

In most cases, SMA is diagnosed based on clinical symptoms and by theabsence of all copies of exon 7 in the SMN1 gene, as determined bygenetic testing. However, in approximately 5% of cases, SMA is caused bymutations other than a deletion of the entire SMN1 gene or other than adeletion of the entire exon 7 in the SMN1 gene, some known and othersnot yet defined. In such cases, when the SMN1 gene test is not feasibleor the SMN1 gene sequence does not show any abnormality, other testssuch as an electromyography (EMG) or muscle biopsy may be indicated.

Medical care for SMA patients at present is limited to supportivetherapy including respiratory, nutritional and rehabilitation care;there is no drug known to address the underlying cause of the disease.Current treatment for SMA consists of prevention and management of thesecondary effects of chronic motor unit loss. The major management issuein Type 1 SMA is the prevention and early treatment of pulmonaryproblems, which are the primary cause of death in the majority of thecases. While some infants afflicted with SMA grow to be adults, thosewith Type 1 SMA have a life expectancy of less than two years.

Several mouse models of SMA have been developed. In particular, theSMNΔ7 model (Le et al., Hum. Mol. Genet., 2005, 14:845) carries both theSMN2 gene and several copies of the SMN2Δ7 cDNA and recapitulates manyof the phenotypic features of Type 1 SMA. The SMNΔ7 model can be usedfor both SMN2 expression studies as well as the evaluation of motorfunction and survival. The C/C-allele mouse model (Jackson Laboratorystrain No.: 008714) provides a less severe SMA disease model, with micehaving reduced levels of both SMN2 full length (SMN2 FL) mRNA and Smnprotein. The C/C-allele mouse phenotype has the SMN2 gene and a hybridmSmn1-SMN2 gene that undergoes alternative splicing, but does not haveovert muscle weakness. The C/C-allele mouse model is used for SMN2expression studies.

As a result of improved understanding of the genetic basis andpathophysiology of SMA, several strategies for treatment have beenexplored, but none have yet demonstrated success in the clinic.

Gene replacement of SMN1, using viral delivery vectors, and cellreplacement, using differentiated SMN1^(+/+) stem cells, havedemonstrated efficacy in animal models of SMA. More research is neededto determine the safety and immune response and to address therequirement for the initiation of treatment at the neonatal stage beforethese approaches can be applied to humans.

Correction of alternative splicing of SMN2 in cultured cells has alsobeen achieved using synthetic nucleic acids as therapeutic agents: (i)antisense oligonucleotides that target sequence elements in SMN2pre-mRNA and shift the outcome of the splicing reaction toward thegeneration of full length SMN2 mRNA (Passini et al., Sci. Transl. Med.,2011, 3:72ra18; and, Hua et al., Nature, 2011, 478:123) and (ii)trans-splicing RNA molecules that provide a fully functional RNAsequence that replace the mutant fragment during splicing and generate afull length SMN1 mRNA (Coady and Lorson, J Neurosci., 2010, 30:126).

Other approaches under exploration include searching for drugs thatincrease Smn levels, enhance residual Smn function, or compensate forloss of Smn. Aminoglycosides have been shown to enhance expression ofstabilized Smn protein produced from SMN2 Δ7 mRNA by promoting thetranslational read-through of the aberrant stop codon, but have poorcentral nervous system penetration and are toxic after repeated dosing.Chemotherapeutic agents, such as aclarubicin, have been shown toincrease Smn protein in cell culture; however, the toxicity profile ofthese drugs prohibits long-term use in SMA patients. Some drugs underclinical investigation for the treatment of SMA include transcriptionactivators such as histone deacetylase (“HDAC”) inhibitors (e.g.,butyrates, valproic acid, and hydroxyurea), and mRNA stabilizers (mRNAdecapping inhibitor RG3039 from Repligen), intended to increase theamount of total RNA transcribed from the SMN2 gene. However, the use ofHDAC inhibitors or mRNA stabilizers does not address the underlyingcause of SMA and may result in a global increase in transcription andgene expression with potential safety problems in humans.

In an alternative approach, neuroprotective agents such as olesoximehave been chosen for investigation. Such strategies are not aimed atincreasing the production of functional Smn for the treatment of SMA,but instead are being explored to protect the Smn-deficient motorneurons from neurodegeneration.

A system designed to identify compounds that increase the inclusion ofexon 7 of SMN into RNA transcribed from the SMN2 gene and certainbenzooxazole and benzoisoxazole compounds identified thereby have beendescribed in International Application PCT/US2009/003238 filed May 27,2009 (published as International Publication Number WO2009/151546 andUnited States Publication Number US2011/0086833). A system designed toidentify compounds that produce a stabilized Smn protein from SMN2 Δ7mRNA and certain isoindolinone compounds identified thereby have beendescribed in International Application PCT/US2009/004625 filed Aug. 13,2009 (published as International Publication Number WO2010/019236 andUnited States Publication Number US2011/0172284). Each of the foregoingdocuments is herein incorporated in their entirety and for all purposes.

All other documents referred to herein are incorporated by referenceinto the present application as though fully set forth herein.

Despite the progress made in understanding the genetic basis andpathophysiology of SMA, there remains a need to identify compounds thatalter the course of spinal muscular atrophy, one of the most devastatingchildhood neurological diseases.

SUMMARY

In one aspect, provided herein are compounds of Formula (I):

or a form thereof, wherein w₁, w₂, w₃, w₄, w₅, w₆ and w₇ are as definedherein. In one embodiment, provided herein is a pharmaceuticalcomposition comprising a compound of Formula (I) or a form thereof, anda pharmaceutically acceptable carrier, excipient or diluent. In aspecific embodiment, provided herein is a compound of Formula (I) or aform thereof, or a pharmaceutical composition thereof for treatingspinal muscular atrophy (SMA).

SMA is caused by deletion or mutation of the SMN1 gene, resulting inselective degeneration of Smn-deficient motor neurons. Although humansubjects retain several copies of the SMN2 gene, the small amount offunctional Smn protein expressed from SMN2 does not fully compensate forthe loss of Smn that would have been expressed from the SMN1 gene. Thecompounds, compositions thereof and uses therewith described herein arebased, in part, on the Applicants discovery that a compound of Formula(I) increases the inclusion of exon 7 of SMN2 into mRNA that istranscribed from an SMN2 minigene. The minigene reproduces thealternative splicing reaction of exon 7 of SMN2 which results in exon 7skipping in the majority of SMN2 transcripts. Thus, compounds of Formula(I) or a form thereof may be used to modulate inclusion of exon 7 ofSMN2 into mRNA that is transcribed from the SMN2 gene. Applicants havealso discovered that a compound of Formula (I) increases the inclusionof exon 7 of SMN1 into mRNA that is transcribed from an SMN1 minigene.Thus, compounds of Formula (I) or a form thereof may be used to modulateinclusion of exon 7 of SMN1 into mRNA that is transcribed from the SMN1gene.

In a specific embodiment, provided herein are compounds of Formula (I)or a form thereof that may be used to modulate the inclusion of exon 7of SMN2 into mRNA that is transcribed from the SMN2 gene. In anotherspecific embodiment, provided herein are compounds of Formula (I) or aform thereof that may be used to modulate the inclusion of exon 7 ofSMN1 into mRNA that is transcribed from the SMN1 gene. In yet anotherembodiment, provided herein are compounds of Formula (I) or a formthereof that may be used to modulate the inclusion of exon 7 of SMN1 andSMN2 into mRNA that is transcribed from the SMN1 and SMN2 genes,respectively.

In another aspect, provided herein is the use of a compound of Formula(I) or a form thereof for treating SMA. In a specific embodiment,provided herein is a method for treating SMA in a human subject in needthereof, comprising administering to the subject an effective amount ofa compound of Formula (I) or a form thereof. The compound of Formula (I)or a form thereof is preferably administered to a human subject in apharmaceutical composition. In another specific embodiment, providedherein is the use of a compound of Formula (I) for treating SMA, whereinthe compound enhances the inclusion of exon 7 of SMN2 into mRNA that istranscribed from the SMN2 gene. Without being limited by theory,compounds of Formula (I) enhance inclusion of exon 7 of SMN2 into mRNAthat is transcribed from the SMN2 gene and increase levels of Smnprotein produced from the SMN2 gene, and thus can be used to treat SMAin a human subject in need thereof.

In another aspect, provided herein are primers and/or probes describedbelow in the Biological Examples (e.g., SMN primers such as SEQ ID NO.1, 7, 8, 11 or 13, and/or SEQ ID NO. 2, 9 or 12, and/or SMN probes suchas a SEQ ID NO. 3 or 10) and the use of those primers and/or probes. Ina specific embodiment, provided herein is an isolated nucleotidesequence comprising SEQ ID NO. 1, 2, 3, 7, 8, 9, 10, 11, 12 or 13. Inanother specific embodiment, provided herein is an isolated nucleotidesequence consisting essentially of SEQ ID NO. 1, 2, 3, 7, 8, 9, 10, 11,12 or 13. In another specific embodiment, provided herein is an isolatednucleotide sequence consisting of SEQ ID NO. 1, 2, 3, 7, 8, 9, 10, 11,12 or 13.

In certain embodiments, the amount of mRNA that is transcribed from theSMN1 gene and/or SMN2 gene and does not include exon 7 of SMN1 and/orSMN2 may be used as a biomarker for SMA, such as disclosed herein. Inother embodiments, the amount of mRNA that is transcribed from the SMN1and/or SMN2 gene and includes exon 7 of SMN1 and/or SMN2 may be used asa biomarker for treating a patient with a compound, such as disclosedherein. In a specific embodiment, the patient is an SMA patient. Inanother specific embodiment, the patient is not an SMA patient.

In certain embodiments, the amount of mRNA that is transcribed from theSMN1 and/or SMN2 gene and includes exon 7 of SMN1 and/or SMN2 as well asthe amount of mRNA that is transcribed from the SMN1 and/or SMN2 geneand does not include exon 7 of SMN1 and/or SMN2 may be used asbiomarkers for treating a patient with a compound, such as disclosedherein. In a specific embodiment, the patient is an SMA patient. Inanother specific embodiment, the patient is not an SMA patient.

In accordance with these embodiments, an SMN primer(s) and/or an SMNprobe described below may be used in assays, such as PCR (e.g., qPCR),rolling circle amplification, and RT-PCR (e.g., endpoint RT-PCR and/orRT-qPCR) to assess and/or quantify the amount of mRNA that istranscribed from the SMN1 gene and/or SMN2 gene and does or does notinclude exon 7 of SMN1 and/or SMN2.

In a specific embodiment, a primer and/or probe described below in theBiological Examples (e.g., SMN primers such as SEQ ID NO. 1, 7, 8, 11 or13 and/or SEQ ID NO. 2, 9 or 12, and/or SMN probes such as a SEQ ID NO.3 or 10) is used in an assay, such as RT-PCR, RT-qPCR, endpoint RT-PCR,PCR, qPCR, rolling circle amplification, Northern blot or Southern blot(e.g., an assay such as described below in the Biological Examples), todetermine whether a compound (e.g., a compound of Formula (I) or a formthereof) enhances the inclusion of exon 7 of SMN2 into mRNA that istranscribed from an SMN2 gene.

In a specific embodiment, a primer and/or probe described below in theBiological Examples (e.g., SMN primers such as SEQ ID NO. 1, 7, 8, 11 or13 and/or SEQ ID NO. 2, 9 or 12, and/or SMN probes such as a SEQ ID NO.3 or 10) is used in an assay, such as RT-PCR, RT-qPCR, endpoint RT-PCR,PCR, qPCR, rolling circle amplification, Northern blot or Southern blot(e.g., an assay such as described below in the Biological Examples), todetermine whether a compound (e.g., a compound of Formula (I) or a formthereof) enhances the inclusion of exon 7 of SMN1 into mRNA that istranscribed from an SMN1 gene.

In a specific embodiment, a primer and/or probe described below in theBiological Examples (e.g., SMN primers such as SEQ ID NO. 1, 7, 8, 11 or13 and/or SEQ ID NO. 2, 9 or 12, and/or SMN probes such as a SEQ ID NO.3 or 10) is used in an assay, such as RT-PCR, RT-qPCR, endpoint RT-PCR,PCR, qPCR, rolling circle amplification, Northern blot or Southern blot(e.g., an assay such as described below in the Biological Examples), todetermine whether a compound (e.g., a compound of Formula (I) or a formthereof) enhances the inclusion of exon 7 of SMN1 and/or SMN2 into mRNAthat is transcribed from an SMN1 and/or SMN2 gene.

In another embodiment, a primer and/or probe described below in theBiological Examples (e.g., SMN primers such as SEQ ID NO. 7, 11 or 13and/or SEQ ID NO. 9 or 12, and/or SMN probes such as a SEQ ID NO. 3 or10) is used in an assay, such as RT-PCR, RT-qPCR, endpoint RT-PCR, PCR,qPCR, rolling circle amplification, Northern blot or Southern blot(e.g., an assay such as described below in the Biological Examples), tomonitor the amount of mRNA that is transcribed from the SMN2 gene andincludes exon 7 of SMN2 in a patient sample. In a specific embodiment,the patient is an SMA patient. In another specific embodiment, thepatient is not an SMA patient.

In another embodiment, a primer and/or probe described below in theBiological Examples (e.g., SMN primers such as SEQ ID NO. 7, 11 or 13and/or SEQ ID NO. 9 or 12, and/or SMN probes such as a SEQ ID NO. 3 or10) is used in an assay, such as RT-PCR, RT-qPCR, endpoint RT-PCR, PCR,qPCR, rolling circle amplification, Northern blot or Southern blot(e.g., an assay such as described below in the Biological Examples), tomonitor the amount of mRNA that is transcribed from the SMN1 gene andincludes exon 7 of SMN1 in a patient sample. In a specific embodiment,the patient is an SMA patient. In another specific embodiment, thepatient is not an SMA patient.

In another embodiment, a primer and/or probe described below in theBiological Examples (e.g., SMN primers such as SEQ ID NO. 7, 11 or 13and/or SEQ ID NO. 9 or 12, and/or SMN probes such as a SEQ ID NO. 3 or10) is used in an assay, such as RT-PCR, RT-qPCR, endpoint RT-PCR, PCR,qPCR, rolling circle amplification, Northern blot or Southern blot(e.g., an assay such as described below in the Biological Examples), tomonitor the amount of mRNA that is transcribed from the SMN1 and/or SMN2gene and includes exon 7 of SMN1 and/or SMN2 in a patient sample. In aspecific embodiment, the patient is an SMA patient. In another specificembodiment, the patient is not an SMA patient.

In another embodiment, a primer and/or probe described below in theBiological Examples (e.g., SMN primers such as SEQ ID NO. 7, 8, 11 or 13and/or SEQ ID NO. 9 or 12, and/or SMN probes such as a SEQ ID NO. 3 or10) is used in an assay, such as RT-PCR, RT-qPCR, endpoint RT-PCR, PCR,qPCR, rolling circle amplification, Northern blot or Southern blot(e.g., an assay such as described below in the Biological Examples), tomonitor a patient's response to a compound (e.g., a compound of Formula(I) or a form thereof). In a specific embodiment, the patient is an SMApatient. In another specific embodiment, the patient is not an SMApatient.

In another embodiment, provided herein is a method for determiningwhether a compound (e.g., a compound of Formula (I) disclosed herein)enhances the inclusion of exon 7 of SMN2 into mRNA that is transcribedfrom the SMN2 gene, comprising (a) contacting mRNA that is transcribedfrom an SMN2 minigene described herein or in International ApplicationPCT/US2009/004625, filed Aug. 13, 2009 (published as InternationalPublication Number WO2010/019236) or United States Publication NumberUS2011/0172284 in the presence of a compound (e.g., a compound ofFormula (I) disclosed herein) with a primer(s) described herein (e.g.,SEQ ID NO. 1 and/or 2) along with applicable components for, e.g.,RT-PCR, RT-qPCR, PCR, endpoint RT-PCR, qPCR or rolling circleamplification; and (b) detecting the amount of mRNA that is transcribedfrom the minigene and includes exon 7 of the SMN2, wherein (1) anincrease in the amount of mRNA that is transcribed from the minigene andincludes exon 7 of SMN2 in the presence of the compound relative to theamount of mRNA that is transcribed from the minigene and includes exon 7of SMN2 in the absence of the compound indicates that the compoundenhances inclusion of exon 7 of SMN2 into mRNA that is transcribed fromthe SMN2 gene; and (2) no change or no substantial change in the amountof mRNA that is transcribed from the minigene and includes exon 7 ofSMN2 in the presence of the compound relative to the amount of mRNA thatis transcribed from the minigene and includes exon 7 of SMN2 in theabsence of the compound indicates that the compound does not enhance theinclusion of exon 7 of SMN2 into mRNA that is transcribed from the SMN2gene.

In another embodiment, provided herein is a method for determiningwhether a compound (e.g., a compound of Formula (I) disclosed herein)enhances the inclusion of exon 7 of SMN1 into mRNA that is transcribedfrom the SMN1 gene, comprising (a) contacting mRNA that is transcribedfrom an SMN1 minigene described in International ApplicationPCT/US2009/004625, filed Aug. 13, 2009 (published as InternationalPublication Number WO2010/019236) or United States Publication NumberUS2011/0172284 in the presence of a compound (e.g., a compound ofFormula (I) disclosed herein) with a primer(s) described herein (e.g.,SEQ ID NO. 1 and/or 2) along with applicable components for, e.g.,RT-PCR, RT-qPCR, PCR, endpoint RT-PCR, qPCR or rolling circleamplification; and (b) detecting the amount of mRNA that is transcribedfrom the minigene and includes exon 7 of the SMN1, wherein (1) anincrease in the amount of mRNA that is transcribed from the minigene andincludes exon 7 of SMN1 in the presence of the compound relative to theamount of mRNA that is transcribed from the minigene and includes exon 7of SMN1 in the absence of the compound indicates that the compoundenhances inclusion of exon 7 of SMN1 into mRNA that is transcribed fromthe SMN1 gene; and (2) no change or no substantial change in the amountof mRNA that is transcribed from the minigene and includes exon 7 ofSMN1 in the presence of the compound relative to the amount of mRNA thatis transcribed from the minigene and includes exon 7 of SMN1 in theabsence of the compound indicates that the compound does not enhance theinclusion of exon 7 of SMN1 into mRNA that is transcribed from the SMN1gene.

In another embodiment, provided herein is a method for determiningwhether a compound (e.g., a compound of Formula (I) disclosed herein)enhances the inclusion of exon 7 of SMN2 into mRNA that is transcribedfrom the SMN2 gene, comprising (a) contacting mRNA that is transcribedfrom an SMN2 minigene described herein or in International ApplicationPCT/US2009/004625, filed Aug. 13, 2009 (published as InternationalPublication Number WO2010/019236) or United States Publication NumberUS2011/0172284 in the presence of a compound (e.g., a compound ofFormula (I) disclosed herein) with a probe described herein (e.g., SEQID NO. 3 or 10) along with applicable components for, e.g., RT-PCR,RT-qPCR, endpoint RT-PCR, PCR, qPCR, rolling circle amplification and,as applicable, Northern blot or Southern blot; and (b) detecting theamount of mRNA that is transcribed from the minigene and includes exon 7of the SMN2, wherein (1) an increase in the amount of mRNA that istranscribed from the minigene and includes exon 7 of SMN2 in thepresence of the compound relative to the amount of mRNA that istranscribed from the minigene and includes exon 7 of SMN2 in the absenceof the compound indicates that the compound enhances inclusion of exon 7of SMN2 into mRNA that is transcribed from the SMN2 gene; and (2) nochange or no substantial change in the amount of mRNA that istranscribed from the minigene and includes exon 7 of SMN2 in thepresence of the compound relative to the amount of mRNA that istranscribed from the minigene and includes exon 7 of SMN2 in the absenceof the compound indicates that the compound does not enhance theinclusion of exon 7 of SMN2 into mRNA that is transcribed from the SMN2gene.

In another embodiment, provided herein is a method for determiningwhether a compound (e.g., a compound of Formula (I) disclosed herein)enhances the inclusion of exon 7 of SMN1 into mRNA that is transcribedfrom the SMN1 gene, comprising (a) contacting mRNA that is transcribedfrom an SMN1 minigene described in International ApplicationPCT/US2009/004625, filed Aug. 13, 2009 (published as InternationalPublication Number WO2010/019236) or United States Publication NumberUS2011/0172284 in the presence of a compound (e.g., a compound ofFormula (I) disclosed herein) with a probe described herein (e.g., SEQID NO. 3 or 10) along with applicable components for, e.g., RT-PCR,RT-qPCR, endpoint RT-PCR, PCR, qPCR, rolling circle amplification and,as applicable, Northern blot or Southern blot; and (b) detecting theamount of mRNA that is transcribed from the minigene and includes exon 7of the SMN1, wherein (1) an increase in the amount of mRNA that istranscribed from the minigene and includes exon 7 of SMN1 in thepresence of the compound relative to the amount of mRNA that istranscribed from the minigene and includes exon 7 of SMN1 in the absenceof the compound indicates that the compound enhances inclusion of exon 7of SMN1 into mRNA that is transcribed from the SMN1 gene; and (2) nochange or no substantial change in the amount of mRNA that istranscribed from the minigene and includes exon 7 of SMN1 in thepresence of the compound relative to the amount of mRNA that istranscribed from the minigene and includes exon 7 of SMN1 in the absenceof the compound indicates that the compound does not enhance theinclusion of exon 7 of SMN2 into mRNA that is transcribed from the SMN2gene.

In another embodiment, provided herein is a method for determiningwhether a compound (e.g., a compound of Formula (I) disclosed herein)enhances the inclusion of exon 7 of SMN2 into mRNA that is transcribedfrom the SMN2 gene, comprising (a) contacting mRNA that is transcribedfrom an SMN2 minigene described herein or in International ApplicationPCT/US2009/004625, filed Aug. 13, 2009 (published as InternationalPublication Number WO2010/019236) or United States Publication NumberUS2011/0172284 in the presence of a compound (e.g., a compound ofFormula (I) disclosed herein) with a primer(s) (e.g., SEQ ID NO. 1 or 2)and/or a probe described herein (e.g., SEQ ID NO. 3 or 10) along withapplicable components for, e.g, RT-PCR, RT-qPCR, endpoint RT-PCR, PCR,qPCR, rolling circle amplification and, as applicable, Northern blot orSouthern blot; and (b) detecting the amount of mRNA that is transcribedfrom the minigene and includes exon 7 of the SMN2, wherein (1) anincrease in the amount of mRNA that is transcribed from the minigene andincludes exon 7 of SMN2 in the presence of the compound relative to theamount of mRNA that is transcribed from the minigene and includes exon 7of SMN2 in the absence of the compound indicates that the compoundenhances inclusion of exon 7 of SMN2 into mRNA that is transcribed fromthe SMN2 gene; and (2) no change or no substantial change in the amountof mRNA that is transcribed from the minigene and includes exon 7 ofSMN2 in the presence of the compound relative to the amount of mRNA thatis transcribed from the minigene and includes exon 7 of SMN2 in theabsence of the compound indicates that the compound does not enhance theinclusion of exon 7 of SMN2 into mRNA that is transcribed from the SMN2gene.

In another embodiment, provided herein is a method for determiningwhether a compound (e.g., a compound of Formula (I) disclosed herein)enhances the inclusion of exon 7 of SMN1 into mRNA that is transcribedfrom the SMN1 gene, comprising (a) contacting mRNA that is transcribedfrom an SMN1 minigene described in International ApplicationPCT/US2009/004625, filed Aug. 13, 2009 (published as InternationalPublication Number WO2010/019236) or United States Publication NumberUS2011/0172284 in the presence of a compound (e.g., a compound ofFormula (I) disclosed herein) with a primer(s) (e.g., SEQ ID NO. 1 or 2)and/or a probe described herein (e.g., SEQ ID NO. 3 or 10) along withapplicable components for, e.g, RT-PCR, RT-qPCR, endpoint RT-PCR, PCR,qPCR, rolling circle amplification and, as applicable, Northern blot orSouthern blot; and (b) detecting the amount of mRNA that is transcribedfrom the minigene and includes exon 7 of the SMN1, wherein (1) anincrease in the amount of mRNA that is transcribed from the minigene andincludes exon 7 of SMN1 in the presence of the compound relative to theamount of mRNA that is transcribed from the minigene and includes exon 7of SMN1 in the absence of the compound indicates that the compoundenhances inclusion of exon 7 of SMN1 into mRNA that is transcribed fromthe SMN1 gene; and (2) no change or no substantial change in the amountof mRNA that is transcribed from the minigene and includes exon 7 ofSMN1 in the presence of the compound relative to the amount of mRNA thatis transcribed from the minigene and includes exon 7 of SMN1 in theabsence of the compound indicates that the compound does not enhance theinclusion of exon 7 of SMN1 into mRNA that is transcribed from the SMN1gene.

In another aspect, provided herein are kits comprising a primer and/orprobe described below in the Biological Examples (e.g., SMN primers suchas SEQ ID NO. 1, 7, 8, 11 or 13 and/or SEQ ID NO. 2, 9 or 12, and/or SMNprobes such as a SEQ ID NO. 3 or 10) and the use thereof.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1, referenced in Biological Example 1, is a schematic drawing ofthe SMN2-A minigene construct, which produces two alternatively splicedmRNA transcripts: a full length mRNA that contains exon 7 and a Δ7 mRNAthat lacks exon 7. The adenine nucleotide inserted in exon 7 of SMN2-Aafter nucleic residue 48 is represented by the letter “A.”Alternatively, the nucleotide may also be selected from cytosine orthymine. Due to the insertion of one nucleotide (A, C, or T) afternucleic residue 48, the full length mRNA does not contain a stop codonin the SMN open reading frame, whereas the Δ7 mRNA has a stop codon inExon 8 that is indicated by the word “Stop.”

FIGS. 2a and 2b , referenced in Biological Example 1, provide the DNAsequence of the minigene from the SMN2-A minigene construct SEQ ID NO.21 (FIG. 2a ). As shown in FIG. 2b , the following sub-sequences can befound:

-   -   1-70: 5′UTR (deg);    -   71-79: exon 6: start codon and BamHI site (atgggatcc);    -   80-190: exon 6;    -   191-5959: intron 6;    -   5960-6014: exon 7 with the adenine nucleotide “A” insert        (position 6008);    -   6015-6458: intron 7;    -   6459-6481: part of exon 8;    -   6482-8146: BamHI site (sequence at the 5′ end), luciferase        coding sequence starting with codon 2 (without initiation        codon), NotI site (sequence at the 3′ end), TAA stop codon; and    -   8147-8266: 3′UTR (deg).

To generate the SMN1 version of the minigene, the sixth nucleotide ofexon 7 (a thymine residue) of the SMN2-A minigene construct is changedto cytosine using site directed mutagenesis. Thus, similar to the SMN2-Aminigene construct, the SMN1 minigene construct has a single adenineresidue inserted after nucleic residue 48 of exon 7. The SMN1 minigeneconstruct is referred to as SMN1-A. Similarly, the nucleotide insertedin the SMN1 minigene construct after nucleic residue 48 of exon 7 mayalso be selected alternatively from cytosine or thymine.

FIGS. 3a and 3b , referenced in Biological Example 2, show thecorrection of SMN2 minigene alternative splicing in cells treated withrising concentrations of Compound 6 (FIG. 3a ) and Compound 170 (FIG. 3b) over a 24 hr period. The levels of full length SMN2 minigene mRNA werequantified using reverse transcription-quantitative PCR (RT-qPCR). Thelevel of full length SMN2 minigene mRNA in compound-treated samples wasnormalized to that in vehicle-treated samples and plotted as a functionof the compound concentration.

FIGS. 4a and 4b , referenced in Biological Example 3, show thecorrection of SMN2 alternative splicing in Type 1 SMA patientfibroblasts treated with rising concentrations of Compound 6 (FIG. 4a )and Compound 170 (FIG. 4b ) over a 24 hr period. The levels of fulllength and Δ7 SMN2 mRNA were quantified using RT-qPCR. The levels offull length and Δ7 SMN2 mRNA in compound-treated samples were normalizedto those in vehicle-treated samples and plotted as a function of thecompound concentration.

FIGS. 5a and 5b , referenced in Biological Example 4, show thecorrection of SMN2 alternative splicing in Type 1 SMA patientfibroblasts treated with rising concentrations of Compound 6 (FIG. 5a )and Compound 170 (FIG. 5b ) over a 24 hr period. The full length and Δ7SMN2 mRNA were amplified using reverse transcription-end point PCR(RT-PCR) and PCR products were separated using agarose gelelectrophoresis. The top and bottom bands correspond to the full lengthand Δ7 SMN2 mRNA respectively. The intensity of each band isproportional to the amount of RNA present in the sample.

FIGS. 6a and 6b , referenced in Biological Example 5, show thecorrection of SMN2 alternative splicing (in both the SMN2 gene and thehybrid mouse Smn1-SMN2 gene) in brain and muscle tissues in a C/C-alleleSMA mouse model resulting from treatment for 10 days twice per day (BID)with 10 mg/kg of Compound 6 (FIG. 6a ) and Compound 170 (FIG. 6b ). Thelevels of full length and Δ7 SMN2 mRNA were quantified using RT-qPCR,the combined full length and Δ7 SMN2 mRNA quantity was set to 1, andfractional quantities of full length and Δ7 SMN2 were calculated.

FIGS. 7a and 7b , referenced in Biological Example 6, show thecorrection of SMN2 alternative splicing (in both the SMN2 gene and thehybrid mouse Smn1-SMN2 gene) in brain and muscle tissues in a C/C-alleleSMA mouse model resulting from treatment for 10 days BID with 10 mg/kgof Compound 6 (FIG. 7a ) and Compound 170 (FIG. 7b ). The full lengthand Δ7 SMN2 mRNA were amplified using RT-PCR. The PCR products wereseparated using agarose gel electrophoresis. The top and bottom bandscorrespond to the full length and Δ7 SMN2 mRNA, respectively. Theintensity of each band is proportional to the amount of RNA present inthe sample.

FIGS. 8a and 8b , referenced in Biological Example 7, show a dosedependent increase in Smn protein expression in SMA Type 1 humanfibroblast cells treated over a 48 hour period with Compound 6 (FIG. 8a) and Compound 170 (FIG. 8b ).

FIGS. 9a and 9b , referenced in Biological Example 8, show an increasein nuclear speckle counts (gems) in Type 1 SMA patient fibroblaststreated with Compound 6 (FIG. 9a ) and Compound 170 (FIG. 9b ) over a 48hour period. Speckles were counted using fluorescence microscopy. Thenumber of speckles in compound-treated samples was normalized to that invehicle-treated samples and plotted as a function of the compoundconcentration.

FIG. 10, referenced in Biological Example 9, shows an increase in Smnprotein expression (black circles) in motor neurons generated from iPScells generated from Type 1 SMA patient fibroblasts treated withCompound 6 (FIG. 10). The level of Smn protein was quantified using Smnimmunostaining and confocal fluorescence microscopy. The level of Smnprotein in compound-treated samples was normalized to that invehicle-treated samples and plotted as a function of the compoundconcentration.

FIGS. 11a and 11b , referenced in Biological Example 11, show increasedSmn protein expression in brain, spinal cord, and muscle tissues in aC/C-allele SMA mouse model resulting from treatment for 10 days BID with100 mg/kg of Compound 6 (FIG. 11a , for n=10) and 10 mg/kg of Compound170 (FIG. 11b , for n=5). The p value by ANOVA in each Figure isindicated with three stars (***) for p<0.001.

FIGS. 12a, 12b, 12c, 12d, 12e, 12f and 12g , referenced in BiologicalExample 12, show a dose dependent increase in Smn protein expression intissues in a neonatal Δ7 SMA mouse model resulting from treatment for 7days once per day (QD) with Compound 6 (brain, FIG. 12a ; spinal cord,FIG. 12b ; muscle, FIG. 12c ; and skin, FIG. 12d , for n=6 to 9) andCompound 170 (brain, FIG. 12e ; spinal cord, FIG. 12f ; muscle, FIG. 12g, for n=7). The p value by ANOVA in each Figure is indicated with onestar (*) for p<0.05, two stars (**) for p<0.01 and three stars (***) forp<0.001.

FIGS. 13a and 13b , referenced in Biological Example 13, showdifferences in body weight in a neonatal Δ7 SMA mouse model resultingfrom treatment up to Postnatal Day (PND) 59 with Compound 6 (FIG. 13a )and until PND 92 with Compound 170 (FIG. 13b ).

FIGS. 14a and 14b , referenced in Biological Example 14, show animproved righting reflex in a neonatal Δ7 SMA mouse model resulting fromtreatment with Compound 6 (FIG. 14a ) and Compound 170 (FIG. 14b ).

FIGS. 15a and 15b , referenced in Biological Example 15, show improvedsurvival in a neonatal Δ7 SMA mouse model resulting from treatment withCompound 6 (FIG. 15a ) and Compound 170 (FIG. 15b ).

FIGS. 16a and 16b , referenced in Biological Example 15, show increasedSmn protein expression in brain, spinal cord, and muscle tissues in a Δ7SMA mouse model resulting from treatment with Compound 6 until PND 156(FIG. 16a ) and with Compound 170 until PND 185 (FIG. 16b ) relative tovehicle treated and age-matched heterozygous mice, respectively.

FIGS. 17a and 17b , referenced in Biological Example 16, show a dosedependent increase in SMN1 minigene FL mRNA and a dose dependentdecrease in SMN1 minigene Δ7 mRNA in HEK293H human cells treated over a7 hour period with Compound 6 (FIG. 17a ) and Compound 170 (FIG. 17b ).The full length and Δ7 SMN1 minigene mRNA were each amplified usingRT-PCR and the resulting PCR products were separated using agarose gelelectrophoresis. The top and bottom bands correspond to the full lengthand Δ7 SMN1 minigene mRNA, respectively. The intensity of each band isproportional to the amount of RNA present in the sample.

DETAILED DESCRIPTION

Provided herein are compounds of Formula (I):

or a form thereof, wherein:

-   -   w₁ and w₅ are independently C—R_(a) or N;    -   w₂ is C—R_(b) or N;    -   w₃, w₄ and w₇ are independently C—R₁, C—R₂, C—R_(a) or N;    -   w₆ is C—R₁, C—R₂, C—R_(c) or N;    -   wherein one of w₃, w₄, w₆ and w₇ is C—R₁ and one other of w₃,        w₄, w₆ and w₇ is C—R₂, provided that,    -   when w₃ is C—R₁, then w₆ is C—R₂ and w₄ and w₇ are independently        C—R_(a) or N; or,    -   when w₃ is C—R₂, then w₆ is C—R₁ and w₄ and w₇ are independently        C—R_(a) or N; or,    -   when w₄ is C—R₁, then w₇ is C—R₂ and w₃ is C—R_(a) or N and w₆        is C—R_(c) or N; or,    -   when w₄ is C—R₂, then w₇ is C—R₁ and w₃ is C—R_(a) or N and w₆        is C—R_(c) or N; and,    -   wherein any one, two or three of w₁, w₂, w₃, w₄, w₅, w₆ and w₇        may optionally be N;    -   R₁ is C₁₋₈alkyl, amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino,        C₁₋₈alkoxy-C₁₋₈alkyl-amino, (C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino,        (C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino, amino-C₁₋₈alkyl,        C₁₋₈alkyl-amino-C₁₋₈alkyl, (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        (C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl,        amino-C₁₋₈alkyl-amino, (amino-C₁₋₈alkyl)₂-amino,        (amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        C₁₋₈alkyl-amino-C₁₋₈alkyl-amino,        (C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,        (C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,        [(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,        amino-C₁₋₈alkoxy, C₁₋₈alkyl-amino-C₁₋₈alkoxy,        (C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,        C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,        C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,        (C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkoxy,        amino-C₂₋₈alkenyl, C₁₋₈alkyl-amino-C₂₋₈alkenyl,        (C₁₋₈alkyl)₂-amino-C₂₋₈alkenyl, amino-C₂₋₈alkynyl,        C₁₋₈alkyl-amino-C₂₋₈alkynyl, (C₁₋₈alkyl)₂-amino-C₂₋₈alkynyl,        halo-C₁₋₈alkyl-amino, (halo-C₁₋₈alkyl)₂-amino,        (halo-C₁₋₈alkyl)(C₁₋₈alkyl)amino, hydroxy-C₁₋₈alkyl,        hydroxy-C₁₋₈alkoxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkyl-amino,        (hydroxy-C₁₋₈alkyl)₂-amino, (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl,        hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,        (hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,        (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkoxy,        hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl-amino,        (hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,        (hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,        (hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl-amino,        [(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,        [(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,        heterocyclyl, heterocyclyl-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkoxy,        heterocyclyl-amino, (heterocyclyl)(C₁₋₈alkyl)amino,        heterocyclyl-amino-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkyl-amino,        (heterocyclyl-C₁₋₈alkyl)₂-amino,        (heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        heterocyclyl-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (heterocyclyl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        (heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl,        heterocyclyl-oxy, heterocyclyl-carbonyl,        heterocyclyl-carbonyl-oxy, C₃₋₁₄cycloalkyl,        aryl-C₁₋₈alkyl-amino, (aryl-C₁₋₈alkyl)₂-amino,        (aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        aryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (aryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        (aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, heteroaryl,        heteroaryl-C₁₋₈alkyl, heteroaryl-C₁₋₈alkoxy, heteroaryl-amino,        heteroaryl-C₁₋₈alkyl-amino, (heteroaryl-C₁₋₈alkyl)₂-amino,        (heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        heteroaryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (heteroaryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl or        (heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl;    -   wherein, each instance of heterocyclyl, C₃₋₁₄cycloalkyl, aryl        and heteroaryl is optionally substituted with one, two or three        R₃ substituents and optionally, with one additional R₄        substituent; or,    -   wherein, each instance of heterocyclyl, C₃₋₁₄cycloalkyl, aryl        and heteroaryl is optionally substituted with one, two, three or        four R₃ substituents;    -   R₂ is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl,        heteroaryl or heteroaryl-amino;    -   wherein, each instance of aryl, heterocyclyl and heteroaryl is        optionally substituted with one, two or three R₆ substituents        and optionally, with one additional R₇ substituent;    -   R_(a) is, in each instance, independently selected from        hydrogen, halogen or C₁₋₈alkyl;    -   R_(b) is hydrogen, halogen, C₁₋₈alkyl or C₁₋₈alkoxy;    -   R_(c) is hydrogen, halogen or C₁₋₈alkyl;    -   R₃ is, in each instance, independently selected from cyano,        halogen, hydroxy, oxo, C₁₋₈alkyl, halo-C₁₋₈alkyl,        C₁₋₈alkyl-carbonyl, C₁₋₈alkoxy, halo-C₁₋₈alkoxy,        C₁₋₈alkoxy-C₁₋₈alkyl, C₁₋₈alkoxy-carbonyl, amino,        C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino, amino-C₁₋₈alkyl,        C₁₋₈alkyl-amino-C₁₋₈alkyl, (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        amino-C₁₋₈alkyl-amino, C₁₋₈alkyl-amino-C₁₋₈alkyl-amino,        (C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,        (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,        [(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl]₂-amino,        (C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        [(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,        C₁₋₈alkoxy-C₁₋₈alkyl-amino, (C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino,        (C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        C₁₋₈alkyl-carbonyl-amino, C₁₋₈alkoxy-carbonyl-amino,        hydroxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkoxy-C₁₋₈alkyl,        hydroxy-C₁₋₈alkyl-amino, (hydroxy-C₁₋₈alkyl)₂-amino or        (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino;    -   R₄ is C₃₋₁₄cycloalkyl, C₃₋₁₄cycloalkyl-C₁₋₈alkyl,        C₃₋₁₄cycloalkyl-amino, aryl-C₁₋₈alkyl, aryl-C₁₋₈alkoxy-carbonyl,        aryl-sulfonyloxy-C₁₋₈alkyl, heterocyclyl or        heterocyclyl-C₁₋₈alkyl; wherein, each instance of        C₃₋₁₄cycloalkyl, aryl and heterocyclyl is optionally substituted        with one, two or three R₅ substituents;    -   R₅ is, in each instance, independently selected from halogen,        hydroxy, cyano, nitro, C₁₋₈alkyl, halo-C₁₋₈alkyl, C₁₋₈alkoxy,        halo-C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino or        C₁₋₈alkyl-thio;    -   R₆ is, in each instance, independently selected from halogen,        hydroxy, cyano, nitro, C₁₋₈alkyl, C₂₋₈alkenyl, halo-C₁₋₈alkyl,        hydroxy-C₁₋₈alkyl, C₁₋₈alkoxy, halo-C₁₋₈alkoxy,        C₁₋₈alkoxy-C₁₋₈alkyl, amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino        or C₁₋₈alkyl-thio; and,    -   R₇ is C₃₋₁₄cycloalkyl, C₃₋₁₄cycloalkyl-oxy, aryl, heterocyclyl        or heteroaryl.

EMBODIMENTS

-   -   In one embodiment of a compound of Formula (I), w₁ is C—R_(a).    -   In another embodiment of a compound of Formula (I), w₁ is N.    -   In one embodiment of a compound of Formula (I), w₂ is C—R_(b).    -   In another embodiment of a compound of Formula (I), w₂ is N.    -   In one embodiment of a compound of Formula (I), w₃ is C—R_(a).    -   In another embodiment of a compound of Formula (I), w₃ is N.    -   In one embodiment of a compound of Formula (I), w₄ is C—R_(a).    -   In another embodiment of a compound of Formula (I), w₄ is N.    -   In one embodiment of a compound of Formula (I), w₅ is C—R_(a).    -   In another embodiment of a compound of Formula (I), w₅ is N.    -   In one embodiment of a compound of Formula (I), w₆ is C—R_(c).    -   In another embodiment of a compound of Formula (I), w₆ is N.    -   In one embodiment of a compound of Formula (I), w₇ is C—R_(a).    -   In another embodiment of a compound of Formula (I), w₇ is N.    -   In one embodiment of a compound of Formula (I), w₃ is C—R₁ and        w₆ is C—R₂.    -   In another embodiment of a compound of Formula (I), w₃ is C—R₂        and w₆ is C—R₁.    -   In one embodiment of a compound of Formula (I), w₄ is C—R₁ and        w₇ is C—R₂.    -   In another embodiment of a compound of Formula (I), w₄ is C—R₂        and w₇ is C—R₁.    -   In one embodiment of a compound of Formula (I), w₃ is C—R₁, w₆        is C—R₂ and w₁, w₄, w₅ and w₇ are independently C—R_(a) or N and        w₂ is C—R_(b) or N.    -   In another embodiment of a compound of Formula (I), w₃ is C—R₂,        w₆ is C—R₁ and w₁, w₄, w₅ and w₇ are independently C—R_(a) or N        and w₂ is C—R_(b) or N.    -   In one embodiment of a compound of Formula (I), w₄ is C—R₁, w₇        is C—R₂, w₁, w₃ and w₅ are independently C—R_(a) or N, w₂ is        C—R_(b) or N and w₆ is C—R_(c) or N.    -   In another embodiment of a compound of Formula (I), w₄ is C—R₂,        w₇ is C—R₁, w₁, w₃ and w₅ are independently C—R_(a) or N, w₂ is        C—R_(b) or N and w₆ is C—R_(c) or N.    -   In one embodiment of a compound of Formula (I), w₁ and w₂ are N.    -   In one embodiment of a compound of Formula (I), w₁ and w₃ are N.    -   In one embodiment of a compound of Formula (I), w₁ and w₄ are N.    -   In one embodiment of a compound of Formula (I), w₁ and w₅ are N.    -   In one embodiment of a compound of Formula (I), w₁ and w₆ are N.    -   In one embodiment of a compound of Formula (I), w₁ and w₇ are N.    -   In one embodiment of a compound of Formula (I),    -   R₁ is C₁₋₈alkyl, amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino,        C₁₋₈alkoxy-C₁₋₈alkyl-amino, (C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino,        (C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino, amino-C₁₋₈alkyl,        C₁₋₈alkyl-amino-C₁₋₈alkyl, (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        (C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl,        amino-C₁₋₈alkyl-amino, (amino-C₁₋₈alkyl)₂-amino,        (amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        C₁₋₈alkyl-amino-C₁₋₈alkyl-amino,        (C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,        (C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,        [(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,        amino-C₁₋₈alkoxy, C₁₋₈alkyl-amino-C₁₋₈alkoxy,        (C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,        C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,        (C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,        (C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkoxy,        amino-C₂₋₈alkenyl, C₁₋₈alkyl-amino-C₂₋₈alkenyl,        (C₁₋₈alkyl)₂-amino-C₂₋₈alkenyl, amino-C₂₋₈alkynyl,        C₁₋₈alkyl-amino-C₂₋₈alkynyl, (C₁₋₈alkyl)₂-amino-C₂₋₈alkynyl,        halo-C₁₋₈alkyl-amino, (halo-C₁₋₈alkyl)₂-amino,        (halo-C₁₋₈alkyl)(C₁₋₈alkyl)amino, hydroxy-C₁₋₈alkyl,        hydroxy-C₁₋₈alkoxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkyl-amino,        (hydroxy-C₁₋₈alkyl)₂-amino, (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl,        hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,        (hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,        (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkoxy,        hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl-amino,        (hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,        (hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,        (hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl-amino,        [(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,        [(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,        heterocyclyl, heterocyclyl-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkoxy,        heterocyclyl-amino, (heterocyclyl)(C₁₋₈alkyl)amino,        heterocyclyl-amino-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkyl-amino,        (heterocyclyl-C₁₋₈alkyl)₂-amino,        (heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        heterocyclyl-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (heterocyclyl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        (heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl,        heterocyclyl-oxy, heterocyclyl-carbonyl,        heterocyclyl-carbonyl-oxy, C₃₋₁₄cycloalkyl,        aryl-C₁₋₈alkyl-amino, (aryl-C₁₋₈alkyl)₂-amino,        (aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        aryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (aryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        (aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, heteroaryl,        heteroaryl-C₁₋₈alkyl, heteroaryl-C₁₋₈alkoxy, heteroaryl-amino,        heteroaryl-C₁₋₈alkyl-amino,        (heteroaryl-C₁₋₈alkyl)₂-amino(heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        heteroaryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (heteroaryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl or        (heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl; wherein, each        instance of heterocyclyl, C₃₋₁₄cycloalkyl, aryl and heteroaryl        is optionally substituted with R₃ and R₄ substituents.    -   In another embodiment of a compound of Formula (I),    -   R₁ is amino, (C₁₋₈alkyl)₂-amino, C₁₋₈alkoxy-C₁₋₈alkyl-amino,        (C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino, amino-C₁₋₈alkyl,        C₁₋₈alkyl-amino-C₁₋₈alkyl, (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        (C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl,        amino-C₁₋₈alkyl-amino, (amino-C₁₋₈alkyl)₂-amino,        (amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        C₁₋₈alkyl-amino-C₁₋₈alkyl-amino,        (C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,        (C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,        [(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,        amino-C₁₋₈alkoxy, C₁₋₈alkyl-amino-C₁₋₈alkoxy,        (C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,        C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,        (C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,        (C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkoxy,        amino-C₂₋₈alkenyl, C₁₋₈alkyl-amino-C₂₋₈alkenyl,        (C₁₋₈alkyl)₂-amino-C₂₋₈alkenyl, amino-C₂₋₈alkynyl,        C₁₋₈alkyl-amino-C₂₋₈alkynyl, (C₁₋₈alkyl)₂-amino-C₂₋₈alkynyl,        halo-C₁₋₈alkyl-amino, (halo-C₁₋₈alkyl)₂-amino,        (halo-C₁₋₈alkyl)(C₁₋₈alkyl)amino, hydroxy-C₁₋₈alkyl,        hydroxy-C₁₋₈alkoxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkyl-amino,        (hydroxy-C₁₋₈alkyl)₂-amino, (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl,        hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,        (hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,        (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkoxy,        hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl-amino,        (hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,        (hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,        (hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl-amino,        [(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,        [(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,        heterocyclyl, heterocyclyl-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkoxy,        heterocyclyl-amino, (heterocyclyl)(C₁₋₈alkyl)amino,        heterocyclyl-amino-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkyl-amino,        (heterocyclyl-C₁₋₈alkyl)₂-amino,        (heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        heterocyclyl-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (heterocyclyl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        (heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl,        heterocyclyl-oxy, heterocyclyl-carbonyl,        heterocyclyl-carbonyl-oxy, C₃₋₁₄cycloalkyl,        aryl-C₁₋₈alkyl-amino, (aryl-C₁₋₈alkyl)₂-amino,        (aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        aryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (aryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        (aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, heteroaryl,        heteroaryl-C₁₋₈alkyl, heteroaryl-C₁₋₈alkoxy,        heteroaryl-C₁₋₈alkyl-amino, (heteroaryl-C₁₋₈alkyl)₂-amino,        (heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        heteroaryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (heteroaryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl or        (heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl; wherein, each        instance of heterocyclyl, C₃₋₁₄cycloalkyl, aryl and heteroaryl        is optionally substituted with R₃ and R₄ substituents.    -   In another embodiment of a compound of Formula (I),    -   R₁ is C₁₋₈alkyl, amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino,        C₁₋₈alkoxy-C₁₋₈alkyl-amino, (C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino,        (C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino, amino-C₁₋₈alkyl,        C₁₋₈alkyl-amino-C₁₋₈alkyl, (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        (C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl,        amino-C₁₋₈alkyl-amino, (amino-C₁₋₈alkyl)₂-amino,        (amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        C₁₋₈alkyl-amino-C₁₋₈alkyl-amino,        (C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,        (C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,        [(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,        amino-C₁₋₈alkoxy, C₁₋₈alkyl-amino-C₁₋₈alkoxy,        (C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,        C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,        (C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,        (C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkoxy,        amino-C₂₋₈alkenyl, C₁₋₈alkyl-amino-C₂₋₈alkenyl,        (C₁₋₈alkyl)₂-amino-C₂₋₈alkenyl, amino-C₂₋₈alkynyl,        C₁₋₈alkyl-amino-C₂₋₈alkynyl, (C₁₋₈alkyl)₂-amino-C₂₋₈alkynyl,        halo-C₁₋₈alkyl-amino, (halo-C₁₋₈alkyl)₂-amino,        (halo-C₁₋₈alkyl)(C₁₋₈alkyl)amino, hydroxy-C₁₋₈alkyl,        hydroxy-C₁₋₈alkoxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkyl-amino,        (hydroxy-C₁₋₈alkyl)₂-amino, (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl,        hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,        (hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,        (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkoxy,        hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl-amino,        (hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,        (hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,        (hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl-amino,        [(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino or        [(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl](C₁₋₈alkyl)amino.    -   In another embodiment of a compound of Formula (I),    -   R₁ is heterocyclyl, heterocyclyl-C₁₋₈alkyl,        heterocyclyl-C₁₋₈alkoxy, heterocyclyl-amino,        (heterocyclyl)(C₁₋₈alkyl)amino, heterocyclyl-amino-C₁₋₈alkyl,        heterocyclyl-C₁₋₈alkyl-amino, (heterocyclyl-C₁₋₈alkyl)₂-amino,        (heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        heterocyclyl-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (heterocyclyl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        (heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl,        heterocyclyl-oxy, heterocyclyl-carbonyl,        heterocyclyl-carbonyl-oxy, C₃₋₁₄cycloalkyl,        aryl-C₁₋₈alkyl-amino, (aryl-C₁₋₈alkyl)₂-amino,        (aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        aryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (aryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        (aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, heteroaryl,        heteroaryl-C₁₋₈alkyl, heteroaryl-C₁₋₈alkoxy, heteroaryl-amino,        heteroaryl-C₁₋₈alkyl-amino,        (heteroaryl-C₁₋₈alkyl)₂-amino(heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        heteroaryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (heteroaryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl or        (heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl; wherein, each        instance of heterocyclyl, C₃₋₁₄cycloalkyl, aryl and heteroaryl        is optionally substituted with R₃ and R₄ substituents.    -   In another embodiment of a compound of Formula (I),    -   R₁ is heterocyclyl, heterocyclyl-C₁₋₈alkyl,        heterocyclyl-C₁₋₈alkoxy, heterocyclyl-amino,        (heterocyclyl)(C₁₋₈alkyl)amino, heterocyclyl-amino-C₁₋₈alkyl,        heterocyclyl-C₁₋₈alkyl-amino, (heterocyclyl-C₁₋₈alkyl)₂-amino,        (heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        heterocyclyl-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (heterocyclyl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        (heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl,        heterocyclyl-oxy, heterocyclyl-carbonyl or        heterocyclyl-carbonyl-oxy; wherein, each instance of        heterocyclyl is optionally substituted with R₃ and R₄        substituents.

In another embodiment of a compound of Formula (I), R₁ is heterocyclyloptionally substituted with R₃ and R₄ substituents.

In another embodiment of a compound of Formula (I), R₁ isC₃₋₁₄cycloalkyl optionally substituted with R₃ and R₄ substituents.

In another embodiment of a compound of Formula (I),

-   -   R₁ is aryl-C₁₋₈alkyl-amino, (aryl-C₁₋₈alkyl)₂-amino,        (aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        aryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (aryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl or        (aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl; wherein, each        instance of aryl is optionally substituted with R₃ and R₄        substituents.

In another embodiment of a compound of Formula (I), R₁ isaryl-C₁₋₈alkyl-amino optionally substituted with R₃ and R₄ substituents.

In another embodiment of a compound of Formula (I),

-   -   R₁ is heteroaryl, heteroaryl-C₁₋₈alkyl, heteroaryl-C₁₋₈alkoxy,        heteroaryl-amino, heteroaryl-C₁₋₈alkyl-amino,        (heteroaryl-C₁₋₈alkyl)₂-amino(heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        heteroaryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (heteroaryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl or        (heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl; wherein, each        instance of heterocyclyl, C₃₋₁₄cycloalkyl, aryl and heteroaryl        is optionally substituted with R₃ and R₄ substituents.

In another embodiment of a compound of Formula (I), R₁ is heteroaryloptionally substituted with R₃ and R₄ substituents.

In one embodiment of a compound of Formula (I),

-   -   R₁ is heterocyclyl selected from azetidinyl, tetrahydrofuranyl,        pyrrolidinyl, piperidinyl, piperazinyl, 1,4-diazepanyl,        1,2,5,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl,        hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl,        (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl,        (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl,        hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl,        (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl,        hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl,        (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl,        octahydro-5H-pyrrolo[3,2-c]pyridinyl,        octahydro-6H-pyrrolo[3,4-b]pyridinyl,        (4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridinyl,        (4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridinyl,        hexahydropyrrolo[1,2-a]pyrazin-(2H)-one,        hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl,        (7R,8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl,        (8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl,        (8aR)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl,        (8aS)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl,        (8aR)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl,        octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[3.1.0]hexyl,        (1R,5S)-3-azabicyclo[3.1.0]hexyl, 8-azabicyclo[3.2.1]octyl,        (1R,5S)-8-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]oct-2-enyl,        (1R,5S)-8-azabicyclo[3.2.1]oct-2-enyl, 9-azabicyclo[3.3.1]nonyl,        (1R,5S)-9-azabicyclo[3.3.1]nonyl, 2,5-diazabicyclo[2.2.1]heptyl,        (1S,4S)-2,5-diazabicyclo[2.2.1]heptyl,        2,5-diazabicyclo[2.2.2]octyl, 3,8-diazabicyclo[3.2.1]octyl,        (1R,5S)-3,8-diazabicyclo[3.2.1]octyl,        1,4-diazabicyclo[3.2.2]nonyl, azaspiro[3.3]heptyl,        2,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[3.5]nonyl,        5,8-diazaspiro[3.5]nonyl, 2,7-diazaspiro[4.4]nonyl or        6,9-diazaspiro[4.5]decyl; wherein, each instance of heterocyclyl        is optionally substituted with R₃ and R₄ substituents.

In another embodiment of a compound of Formula (I),

-   -   R₁ is heterocyclyl selected from azetidin-1-yl,        tetrahydrofuran-3-yl, pyrrolidin-1-yl, piperidin-1-yl,        piperidin-4-yl, piperazin-1-yl, 1,4-diazepan-1-yl,        1,2,5,6-tetrahydropyridin-5-yl, 1,2,3,6-tetrahydropyridin-4-yl,        hexahydropyrrolo[3,4-b]pyrrol-1 (2H)-yl,        (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl,        (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl,        (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl,        hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl,        (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl,        octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl,        octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl,        (4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl,        (4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl,        hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one,        hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl,        (7R,8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl,        (8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl,        (8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl,        (8aS)-octahydropyrrolo[1,2-a]pyrazin-2(1H)-yl,        (8aR)-octahydropyrrolo[1,2-a]pyrazin-2(1H)-yl,        octahydro-2H-pyrido[1,2-a]pyrazin-2-yl,        3-azabicyclo[3.1.0]hex-3-yl, 8-azabicyclo[3.2.1]oct-3-yl,        (1R,5S)-8-azabicyclo[3.2.1]oct-3-yl,        8-azabicyclo[3.2.1]oct-2-en-3-yl,        (1R,5S)-8-azabicyclo[3.2.1]oct-2-en-3-yl,        9-azabicyclo[3.3.1]non-3-yl,        (1R,5S)-9-azabicyclo[3.3.1]non-3-yl,        2,5-diazabicyclo[2.2.1]hept-2-yl,        (1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl,        2,5-diazabicyclo[2.2.2]oct-2-yl,        3,8-diazabicyclo[3.2.1]oct-3-yl,        (1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl,        1,4-diazabicyclo[3.2.2]non-4-yl, azaspiro[3.3]hept-2-yl,        2,6-diazaspiro[3.3]hept-2-yl, 2,7-diazaspiro[3.5]non-7-yl,        5,8-diazaspiro[3.5]non-8-yl, 2,7-diazaspiro[4.4]non-2-yl or        6,9-diazaspiro[4.5]dec-9-yl; wherein, each instance of        heterocyclyl is optionally substituted with R₃ and R₄        substituents.

In another embodiment of a compound of Formula (I),

-   -   R₁ is substituted heterocyclyl selected from        4-methyl-1,4-diazepan-1-yl,        (3aS,6aS)-1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl,        (3aS,6aS)-5-methylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl,        (3aR,6aR)-1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl,        (3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl,        (3aR,6aS)-5-(2-hydroxyethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl,        (3aR,6aS)-5-(propan-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl,        (3aR,6aS)-5-ethylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl,        (4aR,7aR)-1-methyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl,        (4aR,7aR)-1-ethyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl,        (4aR,7aR)-1-(2-hydroxyethyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl,        (4aS,7aS)-1-methyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl,        (4aS,7aS)-1-(2-hydroxyethyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl,        (7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl,        (8aS)-8a-methyloctahydropyrrolo[1,2-a]pyrazin-2(1H)-yl,        (8aR)-8a-methyloctahydropyrrolo[1,2-a]pyrazin-2(1H)-yl,        (1R,5S,6s)-6-(dimethylamino)-3-azabicyclo[3.1.0]hex-3-yl,        (1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl,        9-methyl-9-azabicyclo[3.3.1]non-3-yl,        (3-exo)-9-methyl-9-azabicyclo[3.3.1]non-3-yl,        (1R,5S)-9-methyl-9-azabicyclo[3.3.1]non-3-yl,        (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl or        (1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]hept-2-yl.

In one embodiment of a compound of Formula (I), R₁ isheterocyclyl-C₁₋₈alkyl, wherein heterocyclyl is selected frommorpholinyl, piperidinyl, piperazinyl, imidazolyl or pyrrolidinyl; and,wherein, each instance of heterocyclyl is optionally substituted with R₃and R₄ substituents.

In another embodiment of a compound of Formula (I), R₁ isheterocyclyl-C₁₋₈alkyl selected from morpholin-4-yl-methyl,morpholin-4-yl-ethyl, morpholin-4-yl-propyl, piperidin-1-yl-methyl,piperazin-1-yl-methyl, piperazin-1-yl-ethyl, piperazin-1-yl-propyl,piperazin-1-yl-butyl, imidazol-1-yl-methyl, imidazol-1-yl-ethyl,imidazol-1-yl-propyl, imidazol-1-yl-butyl, pyrrolidin-1-yl-methyl,pyrrolidin-1-yl-ethyl, pyrrolidin-1-yl-propyl or pyrrolidin-1-yl-butyl;wherein, each instance of heterocyclyl is optionally substituted with R₃and R₄ substituents.

In one embodiment of a compound of Formula (I), R₁ isheterocyclyl-C₁₋₈alkoxy, wherein heterocyclyl is selected frompyrrolidinyl, piperidinyl or morpholinyl; and, wherein, each instance ofheterocyclyl is optionally substituted with R₃ and R₄ substituents.

In another embodiment of a compound of Formula (I), R₁ isheterocyclyl-C₁₋₈alkoxy selected from pyrrolidin-2-yl-methoxy,pyrrolidin-2-yl-ethoxy, pyrrolidin-1-yl-methoxy, pyrrolidin-1-yl-ethoxy,piperidin-1-yl-methoxy, piperidin-1-yl-ethoxy, morpholin-4-yl-methoxy ormorpholin-4-yl-ethoxy; wherein, each instance of heterocyclyl isoptionally substituted with R₃ and R₄ substituents.

In one embodiment of a compound of Formula (I), R₁ isheterocyclyl-amino, wherein heterocyclyl is selected from azetidinyl,pyrrolidinyl, piperidinyl, 9-azabicyclo[3.3.1]nonyl or(1R,5S)-9-azabicyclo[3.3.1]nonyl; and, wherein, each instance ofheterocyclyl is optionally substituted with R₃ and R₄ substituents.

In another embodiment of a compound of Formula (I), R₁ isheterocyclyl-amino selected from azetidin-3-yl-amino,pyrrolidin-3-yl-amino, piperidin-4-yl-amino,9-azabicyclo[3.3.1]non-3-yl-amino,(1R,5S)-9-azabicyclo[3.3.1]non-3-yl-amino,9-methyl-9-azabicyclo[3.3.1]non-3-yl-amino,(3-exo)-9-methyl-9-azabicyclo[3.3.1]non-3-yl-amino or(1R,5S)-9-methyl-9-azabicyclo[3.3.1]non-3-yl-amino; wherein, eachinstance of heterocyclyl is optionally substituted with R₃ and R₄substituents.

In one embodiment of a compound of Formula (I), R₁ is(heterocyclyl)(C₁₋₈alkyl)amino, wherein heterocyclyl is selected frompyrrolidinyl or piperidinyl; and, wherein, each instance of heterocyclylis optionally substituted with R₃ and R₄ substituents.

In another embodiment of a compound of Formula (I), R₁ is(heterocyclyl)(C₁₋₈alkyl)amino selected from(pyrrolidin-3-yl)(methyl)amino or (piperidin-4-yl)(methyl)amino;wherein, each instance of heterocyclyl is optionally substituted with R₃and R₄ substituents.

In one embodiment of a compound of Formula (I), R₁ isheterocyclyl-amino-C₁₋₈alkyl, wherein heterocyclyl is selected fromtetrahydrofuranyl; and, wherein, each instance of heterocyclyl isoptionally substituted with R₃ and R₄ substituents.

In another embodiment of a compound of Formula (I), R₁ isheterocyclyl-amino-C₁₋₈alkyl, selected from3-(tetrahydrofuran-3-yl-amino)propyl; wherein, each instance ofheterocyclyl is optionally substituted with R₃ and R₄ substituents.

In one embodiment of a compound of Formula (I), R₁ isheterocyclyl-C₁₋₈alkyl-amino-C₁₋₈alkyl, wherein heterocyclyl is selectedfrom tetrahydrofuranyl, thienyl or pyridinyl; and, wherein, eachinstance of heterocyclyl is optionally substituted with R₃ and R₄substituents.

In another embodiment of a compound of Formula (I), R₁ isheterocyclyl-C₁₋₈alkyl-amino-C₁₋₈alkyl, selected from3-[(tetrahydrofuran-2-ylmethyl)amino]propyl,3-[(thienyl-3-ylmethyl)amino]propyl, 3-[(pyridin-2-ylmethyl)amino]propylor 3-[(pyridin-4-ylmethyl)amino]propyl; wherein, each instance ofheterocyclyl is optionally substituted with R₃ and R₄ substituents.

In one embodiment of a compound of Formula (I), R₁ is heterocyclyl-oxy,wherein heterocyclyl is selected from pyrrolidinyl or piperidinyl; and,wherein, each instance of heterocyclyl is optionally substituted with R₃and R₄ substituents.

In another embodiment of a compound of Formula (I), R₁ isheterocyclyl-oxy selected from pyrrolidin-3-yl-oxy orpiperidin-4-yl-oxy; wherein, each instance of heterocyclyl is optionallysubstituted with R₃ and R₄ substituents.

In one embodiment of a compound of Formula (I), R₁ isheterocyclyl-carbonyl, wherein heterocyclyl is selected frompiperazinyl; and, wherein, each instance of heterocyclyl is optionallysubstituted with R₃ and R₄ substituents.

In another embodiment of a compound of Formula (I), R₁ isheterocyclyl-carbonyl selected from piperazin-1-yl-carbonyl; wherein,each instance of heterocyclyl is optionally substituted with R₃ and R₄substituents.

In one embodiment of a compound of Formula (I), R₁ isheterocyclyl-carbonyl-oxy, wherein heterocyclyl is selected frompiperazinyl; and, wherein, each instance of heterocyclyl is optionallysubstituted with R₃ and R₄ substituents.

In another embodiment of a compound of Formula (I), R₁ isheterocyclyl-carbonyl-oxy selected from piperazin-1-yl-carbonyl-oxy;wherein, each instance of heterocyclyl is optionally substituted with R₃and R₄ substituents.

In one embodiment of a compound of Formula (I), R₁ is C₃₋₁₄cycloalkylselected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cyclohexenyl or cycloheptyl; wherein, each instance of C₃₋₁₄cycloalkylis optionally substituted with R₃ and R₄ substituents.

In another embodiment of a compound of Formula (I), R₁ is C₃₋₈cycloalkylselected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cyclohexenyl or cycloheptyl; wherein, each instance of C₃₋₈cycloalkyl isoptionally substituted with R₃ and R₄ substituents.

In one embodiment of a compound of Formula (I), R₁ isaryl-C₁₋₈alkyl-amino-C₁₋₈alkyl, wherein aryl is selected from phenyl;and, wherein, each instance of aryl is optionally substituted with R₃and R₄ substituents.

In another embodiment of a compound of Formula (I), R₁ isaryl-C₁₋₈alkyl-amino-C₁₋₈alkyl selected from 3-(benzylamino)propyl;wherein, each instance of aryl is optionally substituted with R₃ and R₄substituents.

In one embodiment of a compound of Formula (I), R₁ is heteroaryl,wherein heteroaryl is selected from pyridinyl; and, wherein, eachinstance of heteroaryl is optionally substituted with R₃ and R₄substituents.

In another embodiment of a compound of Formula (I), R₁ is heteroarylselected from pyridin-4-yl; wherein, each instance of heteroaryl isoptionally substituted with R₃ and R₄ substituents.

In one embodiment of a compound of Formula (I), R₁ isheteroaryl-C₁₋₈alkyl, wherein heteroaryl is selected from 1H-imidazolyl;and, wherein, each instance of heteroaryl is optionally substituted withR₃ and R₄ substituents.

In another embodiment of a compound of Formula (I), R₁ isheteroaryl-C₁₋₈alkyl selected from 1H-imidazol-1-yl-methyl; wherein,each instance of heteroaryl is optionally substituted with R₃ and R₄substituents.

In one embodiment of a compound of Formula (I), R₁ is(heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino, wherein heteroaryl is selectedfrom pyridinyl; and, wherein, each instance of heteroaryl is optionallysubstituted with R₃ and R₄ substituents.

In another embodiment of a compound of Formula (I), R₁ is(heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino selected from(pyridin-3-ylmethyl)(methyl)amino; wherein, each instance of heteroarylis optionally substituted with R₃ and R₄ substituents.

In one embodiment of a compound of Formula (I), R₁ isheteroaryl-C₁₋₈alkyl-amino-C₁₋₈alkyl, wherein heteroaryl is selectedfrom thienyl or pyridinyl; and, wherein, each instance of heteroaryl isoptionally substituted with R₃ and R₄ substituents.

In another embodiment of a compound of Formula (I), R₁ isheteroaryl-C₁₋₈alkyl-amino-C₁₋₈alkyl selected fromthien-3-yl-methyl-amino-propyl, pyridin-2-yl-methyl-amino-propyl,pyridin-3-yl-methyl-amino-propyl or pyridin-4-yl-methyl-amino-propyl;wherein, each instance of heteroaryl is optionally substituted with R₃and R₄ substituents.

In one embodiment of a compound of Formula (I), R₃ is selected fromcyano, halogen, hydroxy, oxo, C₁₋₈alkyl, halo-C₁₋₈alkyl,C₁₋₈alkyl-carbonyl, C₁₋₈alkoxy, halo-C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl,C₁₋₈alkoxy-carbonyl, amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino,amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl,(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl, amino-C₁₋₈alkyl-amino,C₁₋₈alkyl-amino-C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,C₁₋₈alkoxy-C₁₋₈alkyl-amino, C₁₋₈alkyl-carbonyl-amino,C₁₋₈alkoxy-carbonyl-amino, hydroxy-C₁₋₈alkyl,hydroxy-C₁₋₈alkoxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkyl-amino,(hydroxy-C₁₋₈alkyl)₂-amino or (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino.

In another embodiment of a compound of Formula (I), R₃ is selected fromcyano, halogen, hydroxy, oxo, C₁₋₈alkyl, halo-C₁₋₈alkyl, C₁₋₈alkoxy,C₁₋₈alkoxy-C₁₋₈alkyl, C₁₋₈alkoxy-carbonyl, amino, C₁₋₈alkyl-amino,(C₁₋₈alkyl)₂-amino, amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl,(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl-amino,C₁₋₈alkoxy-C₁₋₈alkyl-amino, C₁₋₈alkoxy-carbonyl-amino,hydroxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkoxy-C₁₋₈alkyl,hydroxy-C₁₋₈alkyl-amino, (hydroxy-C₁₋₈alkyl)₂-amino or(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino.

In one embodiment of a compound of Formula (I), R₃ is C₁₋₈alkyl selectedfrom methyl, ethyl, propyl, isopropyl or tert-butyl.

In another embodiment of a compound of Formula (I), R₃ is C₁₋₈alkylselected from ethyl, propyl, isopropyl or tert-butyl.

In one embodiment of a compound of Formula (I), R₃ is halo-C₁₋₈alkylselected from trihalo-methyl, dihalo-methyl, halo-methyl, trihalo-ethyl,dihalo-ethyl, halo-ethyl, trihalo-propyl, dihalo-propyl or halo-propyl;wherein, halo is selected from fluoro, chloro, bromo or iodo.

In another embodiment of a compound of Formula (I), R₃ is halo-C₁₋₈alkylselected from trihalo-methyl, dihalo-methyl, halo-methyl, trihalo-ethyl,dihalo-ethyl, trihalo-propyl or dihalo-propyl; wherein, halo is selectedfrom fluoro, chloro, bromo or iodo.

In one embodiment of a compound of Formula (I), R₃ is hydroxy-C₁₋₈alkylselected from hydroxy-methyl, hydroxy-ethyl, hydroxy-propyl,dihydroxy-propyl, hydroxy-butyl or dihydroxy-butyl.

In another embodiment of a compound of Formula (I), R₃ ishydroxy-C₁₋₈alkyl selected from hydroxy-methyl, dihydroxy-propyl,hydroxy-butyl or dihydroxy-butyl.

In one embodiment of a compound of Formula (I), R₃ is C₁₋₈alkoxyselected from methoxy, ethoxy, propoxy or isopropoxy.

In one embodiment of a compound of Formula (I), R₃ is halo-C₁₋₈alkoxyselected from trihalo-methoxy, dihalo-methoxy, halo-methoxy,trihalo-ethoxy, dihalo-ethoxy, halo-ethoxy, trihalo-propoxy,dihalo-propoxy or halo-propoxy; wherein, halo is selected from fluoro,chloro, bromo or iodo.

In one embodiment of a compound of Formula (I), R₃ isC₁₋₈alkoxy-carbonyl-amino selected from methoxy-carbonyl-amino,ethoxy-carbonyl-amino, propoxy-carbonyl-amino,isopropoxy-carbonyl-amino, tert-butoxy-carbonyl-amino.

In one embodiment of a compound of Formula (I), R₄ is C₃₋₁₄cycloalkylselected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl orcycloheptyl; wherein, each instance of C₃₋₁₄cycloalkyl is optionallysubstituted with R₅ substituents.

In another embodiment of a compound of Formula (I), R₄ is C₃₋₈cycloalkylselected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl orcycloheptyl; wherein, each instance of C₃₋₈cycloalkyl is optionallysubstituted with R₅ substituents.

In one embodiment of a compound of Formula (I), R₄ isC₃₋₁₄cycloalkyl-C₁₋₈alkyl, wherein C₃₋₁₄cycloalkyl is selected fromcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; and,wherein, each instance of C₃₋₁₄cycloalkyl is optionally substituted withR₅ substituents.

In another embodiment of a compound of Formula (I), R₄ isC₃₋₈cycloalkyl-C₁₋₈alkyl, wherein C₃₋₈cycloalkyl is selected fromcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; and,wherein, each instance of C₃₋₈cycloalkyl is optionally substituted withR₅ substituents.

In one embodiment of a compound of Formula (I), R₄ isC₃₋₁₄cycloalkyl-amino, wherein C₃₋₁₄cycloalkyl is selected fromcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; and,wherein, each instance of C₃₋₁₄cycloalkyl is optionally substituted withR₅ substituents.

In another embodiment of a compound of Formula (I), R₄ isC₃₋₈cycloalkyl-amino, wherein C₃₋₈cycloalkyl is selected fromcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; and,wherein, each instance of C₃₋₈cycloalkyl is optionally substituted withR₅ substituents.

In one embodiment of a compound of Formula (I), R₄ is aryl-C₁₋₈alkyl,aryl-C₁₋₈alkoxy-carbonyl or aryl-sulfonyloxy-C₁₋₈alkyl, wherein aryl isselected from phenyl; and, wherein, each instance of aryl is optionallysubstituted with R₅ substituents.

In another embodiment of a compound of Formula (I), R₄ is aryl-C₁₋₈alkylor aryl-C₁₋₈alkoxy-carbonyl, wherein each instance of aryl is optionallysubstituted with R₅ substituents.

In one embodiment of a compound of Formula (I), R₄ is heterocyclylselected from oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl,1,3-dioxanyl or morpholinyl, wherein each instance of heterocyclyl isoptionally substituted with R₅ substituents.

In another embodiment of a compound of Formula (I), R₄ is heterocyclylselected from oxetan-3-yl, pyrrolidin-1-yl, piperidin-1-yl,piperazin-1-yl, 1,3-dioxan-5-yl or morpholin-4-yl, wherein each instanceof heterocyclyl is optionally substituted with R₅ substituents.

In one embodiment of a compound of Formula (I), R₄ isheterocyclyl-C₁₋₈alkyl, wherein each instance of heterocyclyl isselected from pyrrolidinyl or piperidinyl; and, wherein, each instanceof heterocyclyl is optionally substituted with R₅ substituents.

In another embodiment of a compound of Formula (I), R₄ isheterocyclyl-C₁₋₈alkyl selected from pyrrolidin-1-yl-C₁₋₈alkyl orpiperidin-1-yl-C₁₋₈alkyl, wherein each instance of heterocyclyl isoptionally substituted with R₅ substituents.

In one embodiment of a compound of Formula (I), R₅ is selected fromhalogen, hydroxy, cyano, nitro, halo-C₁₋₈alkyl, C₁₋₈alkoxy,halo-C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino orC₁₋₈alkyl-thio; wherein, halogen and halo is selected from fluoro,chloro, bromo or iodo.

In one embodiment of a compound of Formula (I), R₅ is hydroxy.

In one embodiment of a compound of Formula (I), R₅ is C₁₋₈alkyl selectedfrom methyl, ethyl, propyl, isopropyl, n-butyl or tert-butyl.

In another embodiment of a compound of Formula (I), R₅ is C₁₋₈alkylselected from ethyl, propyl, isopropyl or tert-butyl.

In one embodiment of a compound of Formula (I), R₅ is halo-C₁₋₈alkylselected from trihalo-methyl, dihalo-methyl, halo-methyl, trihalo-ethyl,dihalo-ethyl, halo-ethyl, trihalo-propyl, dihalo-propyl or halo-propyl;wherein, halo is selected from fluoro, chloro, bromo or iodo.

In one embodiment of a compound of Formula (I), R₅ is C₁₋₈alkoxyselected from methoxy, ethoxy, propoxy or isopropoxy.

In one embodiment of a compound of Formula (I), R₅ is halo-C₁₋₈alkoxyselected from trihalo-methoxy, dihalo-methoxy, halo-methoxy,trihalo-ethoxy, dihalo-ethoxy, halo-ethoxy, trihalo-propoxy,dihalo-propoxy or halo-propoxy; wherein, halo is selected from fluoro,chloro, bromo or iodo.

In one embodiment of a compound of Formula (I), R₂ is aryl selected fromphenyl optionally substituted with R₆ and R₇ substituents.

In one embodiment of a compound of Formula (I), R₂ is aryl-amino,wherein aryl is selected from phenyl; and, wherein, each instance ofaryl is optionally substituted with R₆ and R₇ substituents.

In another embodiment of a compound of Formula (I), R₂ is aryl-aminoselected from phenyl-amino; wherein, each instance of aryl is optionallysubstituted with R₆ and R₇ substituents.

In one embodiment of a compound of Formula (I), R₂ isaryl-amino-carbonyl, wherein aryl is selected from phenyl; and, wherein,each instance of aryl is optionally substituted with R₆ and R₇substituents.

In another embodiment of a compound of Formula (I), R₂ isaryl-amino-carbonyl selected from phenyl-amino-carbonyl; wherein, eachinstance of aryl is optionally substituted with R₆ and R₇ substituents.

In one embodiment of a compound of Formula (I),

-   -   R₂ is heterocyclyl selected from 1,2,3,6-tetrahydropyridinyl,        1,3-benzodioxolyl or 2,3-dihydro-1,4-benzodioxinyl; wherein,        each instance of heterocyclyl is optionally substituted with R₆        and R₇ substituents.

In another embodiment of a compound of Formula (I),

-   -   R₂ is heterocyclyl selected from 1,2,3,6-tetrahydropyridin-4-yl,        1,3-benzodioxol-5-yl or 2,3-dihydro-1,4-benzodioxin-6-yl;        wherein, each instance of heterocyclyl is optionally substituted        with R₆ and R₇ substituents.

In one embodiment of a compound of Formula (I),

-   -   R₂ is heteroaryl selected from thienyl, 1H-pyrazolyl,        1H-imidazolyl, 1,3-thiazolyl, 1,2,4-oxadiazolyl,        1,3,4-oxadiazolyl, pyridinyl, pyrimidinyl, 1H-indolyl,        2H-indolyl, 1H-indazolyl, 2H-indazolyl, indolizinyl,        benzofuranyl, benzothienyl, 1H-benzimidazolyl,        1,3-benzothiazolyl, 1,3-benzoxazolyl, 9H-purinyl,        furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl,        furo[2,3-c]pyridinyl, thieno[3,2-c]pyridinyl,        thieno[2,3-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl,        1H-pyrrolo[2,3-c]pyridinyl, pyrrolo[1,2-a]pyrimidinyl,        pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-b]pyridazinyl,        pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrazinyl,        imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrimidinyl,        imidazo[1,2-c]pyrimidinyl, imidazo[1,2-b]pyridazinyl,        imidazo[1,2-a]pyrazinyl, imidazo[2,1-b][1,3]thiazolyl,        imidazo[2,1-b][1,3,4]thiadiazolyl, [1,3]oxazolo[4,5-b]pyridinyl        or quinoxalinyl; wherein, each instance of heteroaryl is        optionally substituted with R₆ and R₇ substituents.

In another embodiment of a compound of Formula (I),

-   -   R₂ is heteroaryl selected from thien-2-yl, thien-3-yl,        1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl,        1H-imidazol-1-yl, 1H-imidazol-4-yl, 1,3-thiazol-2-yl,        1,2,4-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, pyridin-2-yl,        pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl, 1H-indol-3-yl,        1H-indol-4-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H-indazol-5-yl,        2H-indazol-5-yl, indolizin-2-yl, benzofuran-2-yl,        benzofuran-5-yl, benzothien-2-yl, benzothien-3-yl,        1H-benzimidazol-2-yl, 1H-benzimidazol-6-yl, 1,3-benzoxazol-2-yl,        1,3-benzoxazol-5-yl, 1,3-benzoxazol-6-yl, 1,3-benzothiazol-2-yl,        1,3-benzothiazol-5-yl, 1,3-benzothiazol-6-yl, 9H-purin-8-yl,        furo[3,2-b]pyridin-2-yl, furo[3,2-c]pyridin-2-yl,        furo[2,3-c]pyridin-2-yl, thieno[3,2-c]pyridin-2-yl,        thieno[2,3-d]pyrimidin-6-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl,        1H-pyrrolo[2,3-c]pyridin-4-yl, pyrrolo[1,2-a]pyrimidin-7-yl,        pyrrolo[1,2-a]pyrazin-7-yl, pyrrolo[1,2-b]pyridazin-2-yl,        pyrazolo[1,5-a]pyridin-2-yl, pyrazolo[1,5-a]pyrazin-2-yl,        imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-a]pyridin-6-yl,        imidazo[1,2-a]pyrimidin-2-yl, imidazo[1,2-a]pyrimidin-6-yl,        imidazo[1,2-c]pyrimidin-2-yl, imidazo[1,2-b]pyridazin-2-yl,        imidazo[1,2-a]pyrazin-2-yl, imidazo[2,1-b][1,3]thiazol-6-yl,        imidazo[2,1-b][1,3,4]thiadiazol-6-yl,        [1,3]oxazolo[4,5-b]pyridin-2-yl or quinoxalin-2-yl; wherein,        each instance of heteroaryl is optionally substituted with R₆        and R₇ substituents.

In another embodiment of a compound of Formula (I),

-   -   R₂ is substituted heteroaryl selected from 4-methylthien-2-yl,        1-methyl-1H-pyrazol-3-yl, 4-methyl-1H-pyrazol-3-yl,        1-phenyl-1H-pyrazol-3-yl, 1-phenyl-1H-imidazol-4-yl,        2-methyl-1-(pyridin-2-yl)-1H-imidazol-4-yl,        4-methyl-1,3-thiazol-2-yl, 4-(trifluoromethyl)-1,3-thiazol-2-yl,        4-phenyl-1,3-thiazol-2-yl, 5-phenyl-1,2,4-oxadiazol-3-yl,        3-fluoropyridin-4-yl, 6-fluoropyridin-2-yl,        2-chloropyridin-4-yl, 4-chloropyridin-3-yl,        5-chloropyridin-2-yl, 6-methylpyridin-3-yl,        2-(trifluoromethyl)pyridin-3-yl,        4-(trifluoromethyl)pyridin-2-yl,        6-(trifluoromethyl)pyridin-2-yl, 2-methoxypyridin-4-yl,        4-methoxypyridin-3-yl, 6-methoxypyridin-2-yl,        2-ethoxypyridin-3-yl, 6-ethoxypyridin-2-yl,        6-(propan-2-yloxy)pyridin-2-yl, 6-(dimethylamino)pyridin-3-yl,        6-(methylsulfanyl)pyridin-2-yl, 6-(cyclobutyloxy)pyridin-2-yl,        6-(pyrrolidin-1-yl)pyridin-2-yl, 2-methylpyrimidin-4-yl,        2-(propan-2-yl)pyrimidin-4-yl, 2-cyclopropylpyrimidin-4-yl,        1-methyl-1H-indol-3-yl, 2-methyl-2H-indazol-5-yl,        2-methyl-1-benzofuran-5-yl, 1-methyl-1H-benzimidazol-2-yl,        4-methyl-1H-benzimidazol-2-yl 5-fluoro-1H-benzimidazol-2-yl,        4-fluoro-1,3-benzoxazol-2-yl, 5-fluoro-1,3-benzoxazol-2-yl,        4-chloro-1,3-benzoxazol-2-yl, 4-iodo-1,3-benzoxazol-2-yl,        2-methyl-1,3-benzoxazol-6-yl, 4-methyl-1,3-benzoxazol-2-yl,        4-(trifluoromethyl)-1,3-benzoxazol-2-yl,        7-(trifluoromethyl)-1,3-benzoxazol-2-yl,        2-methyl-1,3-benzothiazol-2-yl, 2-methyl-1,3-benzothiazol-5-yl,        2-methyl-1,3-benzothiazol-6-yl, 4-chloro-1,3-benzothiazol-2-yl,        7-chloro-1,3-benzothiazol-2-yl,        4-(trifluoromethyl)-1,3-benzothiazol-2-yl,        5-methylfuro[3,2-b]pyridin-2-yl,        4,6-dimethylfuro[3,2-c]pyridin-2-yl,        5,7-dimethylfuro[2,3-c]pyridin-2-yl,        4,6-dimethylthieno[3,2-c]pyridin-2-yl,        2,4-dimethylthieno[2,3-d]pyrimidin-6-yl,        1-methylpyrrolo[1,2-a]pyrazin-7-yl,        3-methylpyrrolo[1,2-a]pyrazin-7-yl,        1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl,        2-methylpyrrolo[1,2-b]pyridazin-2-yl,        4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl,        5-methylpyrazolo[1,5-a]pyridin-2-yl,        4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl, 2-chloroimidazo[2,        1-b][1,3]thiazol-6-yl, 2-methylimidazo[2, 1-b][1,3]thiazol-6-yl,        3-methylimidazo[2, l-b][1,3]thiazol-6-yl,        2-ethylimidazo[2,1-b][1,3]thiazol-6-yl, 2-methylimidazo[2,        1-b][1,3,4]thiadiazol-6-yl, 6-cyanoimidazo[1,2-a]pyridin-2-yl        (also referred to as 2-imidazo[1,2-a]pyridine-6-carbonitrile),        6-fluoroimidazo[1,2-a]pyridin-2-yl,        8-fluoroimidazo[1,2-a]pyridin-2-yl,        6,8-difluoroimidazo[1,2-a]pyridin-2-yl,        7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl,        8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl,        6-chloroimidazo[1,2-a]pyridin-2-yl,        7-chloroimidazo[1,2-a]pyridin-2-yl,        8-chloroimidazo[1,2-a]pyridin-2-yl,        8-bromoimidazo[1,2-a]pyridin-2-yl,        2-methylimidazo[1,2-a]pyridin-2-yl,        5-methylimidazo[1,2-a]pyridin-2-yl,        6-methylimidazo[1,2-a]pyridin-2-yl,        7-methylimidazo[1,2-a]pyridin-2-yl,        8-methylimidazo[1,2-a]pyridin-2-yl,        7-ethylimidazo[1,2-a]pyridin-2-yl,        8-ethylimidazo[1,2-a]pyridin-2-yl,        6,8-dimethylimidazo[1,2-a]pyridin-2-yl,        8-ethyl-6-methylimidazo[1,2-a]pyridin-2-yl,        7-methoxyimidazo[1,2-a]pyridin-2-yl,        8-methoxyimidazo[1,2-a]pyridin-2-yl,        6-fluoro-8-methylimidazo[1,2-a]pyridin-2-yl,        8-fluoro-6-methylimidazo[1,2-a]pyridin-2-yl,        8-chloro-6-methylimidazo[1,2-a]pyridin-2-yl,        6-methyl-8-nitroimidazo[1,2-a]pyridin-2-yl,        8-cyclopropylimidazo[1,2-a]pyridin-2-yl,        2-methylimidazo[1,2-a]pyridin-6-yl,        2-ethylimidazo[1,2-a]pyridin-6-yl,        2,3-dimethylimidazo[1,2-a]pyridin-6-yl,        2,8-dimethylimidazo[1,2-a]pyridin-6-yl,        2-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl,        8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl,        8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl,        6-fluoroimidazo[1,2-a]pyrimidin-2-yl,        6-chloroimidazo[1,2-a]pyrimidin-2-yl,        6-methylimidazo[1,2-a]pyrimidin-2-yl,        7-methylimidazo[1,2-a]pyrimidin-2-yl,        2-methylimidazo[1,2-a]pyrimidin-6-yl,        6-methylimidazo[1,2-b]pyridazin-2-yl,        2-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl,        6-methylimidazo[1,2-a]pyrazin-2-yl,        8-methylimidazo[1,2-a]pyrazin-2-yl,        6,8-dimethylimidazo[1,2-a]pyrazin-2-yl,        6-chloro-8-methylimidazo[1,2-a]pyrazin-2-yl,        6-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyrazin-2-yl,        8-(methyl sulfanyl)imidazo[1,2-a]pyrazin-2-yl,        2-methylimidazo[2, 1-b][1,3]thiazol-6-yl, 3-methylimidazo[2,        1-b][1,3]thiazol-6-yl or 2-methylimidazo[2,        1-b][1,3,4]thiadiazol-6-yl.

In another embodiment of a compound of Formula (I),

-   -   R₂ is heteroaryl selected from thienyl, 1H-pyrazolyl,        1H-imidazolyl, 1,3-thiazolyl, 1,2,4-oxadiazolyl,        1,3,4-oxadiazolyl, pyridinyl, pyrimidinyl, 1H-indolyl,        2H-indolyl, 1H-indazolyl, 2H-indazolyl, indolizinyl,        benzofuranyl, benzothienyl, 1H-benzimidazolyl,        1,3-benzothiazolyl, 1,3-benzoxazolyl, 9H-purinyl; wherein, each        instance of heteroaryl is optionally substituted with R₆ and R₇        substituents.

In another embodiment of a compound of Formula (I),

-   -   R₂ is heteroaryl selected from furo[3,2-b]pyridinyl,        furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl,        thieno[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl,        1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl,        pyrrolo[1,2-a]pyrimidinyl, pyrrolo[1,2-a]pyrazinyl,        pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridinyl,        pyrazolo[1,5-a]pyrazinyl, imidazo[1,2-a]pyridinyl,        imidazo[1,2-a]pyrimidinyl, imidazo[1,2-c]pyrimidinyl,        imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl,        imidazo[2,1-b][1,3]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl,        [1,3]oxazolo[4,5-b]pyridinyl or quinoxalinyl; wherein, each        instance of heteroaryl is optionally substituted with R₆ and R₇        substituents.

In one embodiment of a compound of Formula (I), R₂ is heteroaryl-amino,wherein heteroaryl is selected from pyridinyl or pyrimidinyl; and,wherein, each instance of heteroaryl is optionally substituted with R₆and R₇ substituents.

In another embodiment of a compound of Formula (I), R₂ isheteroaryl-amino selected from pyridin-2-yl-amino, pyridin-3-yl-amino orpyrimidin-2-yl-amino; wherein, each instance of heteroaryl is optionallysubstituted with R₆ and R₇ substituents.

In one embodiment of a compound of Formula (I), R₆ is selected fromhalogen, hydroxy, cyano, nitro, C₁₋₈alkyl, halo-C₁₋₈alkyl,hydroxy-C₁₋₈alkyl, C₁₋₈alkoxy, halo-C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl,(C₁₋₈alkyl)₂-amino or C₁₋₈alkyl-thio; wherein, halogen and halo isselected from fluoro, chloro, bromo or iodo.

In one embodiment of a compound of Formula (I), R₆ is C₁₋₈alkyl selectedfrom methyl, ethyl, propyl, isopropyl or tert-butyl.

In another embodiment of a compound of Formula (I), R₆ is C₁₋₈alkylselected from ethyl, propyl, isopropyl or tert-butyl.

In one embodiment of a compound of Formula (I), R₆ is C₂₋₈alkenylselected from ethenyl, allyl or buta-1,3-dienyl.

In another embodiment of a compound of Formula (I), R₆ is C₂₋₈alkenylselected from ethenyl or allyl.

In one embodiment of a compound of Formula (I), R₆ is halo-C₁₋₈alkylselected from trihalo-methyl, dihalo-methyl, halo-methyl, trihalo-ethyl,dihalo-ethyl, halo-ethyl, trihalo-propyl, dihalo-propyl or halo-propyl;wherein, halo is selected from fluoro, chloro, bromo or iodo.

In one embodiment of a compound of Formula (I), R₆ is hydroxy-C₁₋₈alkylselected from hydroxy-methyl, hydroxy-ethyl, hydroxy-propyl,dihydroxy-propyl, hydroxy-butyl or dihydroxy-butyl.

In another embodiment of a compound of Formula (I), R₆ ishydroxy-C₁₋₈alkyl selected from hydroxy-methyl, dihydroxy-propyl,hydroxy-butyl or dihydroxy-butyl.

In one embodiment of a compound of Formula (I), R₆ is C₁₋₈alkoxyselected from methoxy, ethoxy, propoxy or isopropoxy.

In one embodiment of a compound of Formula (I), R₆ is halo-C₁₋₈alkoxyselected from trihalo-methoxy, dihalo-methoxy, halo-methoxy,trihalo-ethoxy, dihalo-ethoxy, halo-ethoxy, trihalo-propoxy,dihalo-propoxy or halo-propoxy; wherein, halo is selected from fluoro,chloro, bromo or iodo.

In one embodiment of a compound of Formula (I), R₇ is C₃₋₁₄cycloalkyl,C₃₋₁₄cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl; whereinC₃₋₁₄cycloalkyl is selected from cyclopropyl or cyclobutoxy; whereinaryl is selected from phenyl; wherein heterocyclyl is selected fromoxetanyl, pyrrolidinyl or 1,2,3,6-tetrahydropyridinyl; and, whereinheteroaryl is selected from thienyl or pyridinyl.

In another embodiment of a compound of Formula (I), R₇ isC₃₋₁₄cycloalkyl or C₃₋₁₄cycloalkyl-oxy, wherein each instance ofC₃₋₁₄cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or cycloheptyl.

In another embodiment of a compound of Formula (I), R₇ is C₃₋₈cycloalkylor C₃₋₈cycloalkyl-oxy, wherein each instance of C₃₋₈cycloalkyl isselected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl orcycloheptyl.

In one embodiment of a compound of Formula (I), R₇ is aryl selected fromphenyl.

In one embodiment of a compound of Formula (I), R₇ is heterocyclylselected from oxetanyl, pyrrolidinyl or 1,2,3,6-tetrahydropyridinyl.

In another embodiment of a compound of Formula (I), R₇ is heterocyclylselected from oxetan-3-yl, pyrrolidin-1-yl or1,2,3,6-tetrahydropyridin-4-yl.

In one embodiment of a compound of Formula (I), R₇ is heteroarylselected from thienyl or pyridinyl.

In another embodiment of a compound of Formula (I), R₇ is heteroarylselected from pyridinyl.

In one embodiment of a compound of Formula (I), R₇ is heteroarylselected from thien-2-yl or pyridin-2-yl.

In another embodiment of a compound of Formula (I), R₇ is heteroarylselected from pyridin-2-yl.

In one embodiment of a compound of Formula (I), R_(c) is hydrogen orC₁₋₈alkyl.

In another embodiment of a compound of Formula (I),

-   -   R₁ is heterocyclyl, heterocyclyl-C₁₋₈alkyl,        heterocyclyl-C₁₋₈alkoxy, heterocyclyl-amino,        (heterocyclyl)(C₁₋₈alkyl)amino, heterocyclyl-amino-C₁₋₈alkyl,        heterocyclyl-C₁₋₈alkyl-amino, (heterocyclyl-C₁₋₈alkyl)₂-amino,        (heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        heterocyclyl-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (heterocyclyl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        (heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl,        heterocyclyl-oxy, heterocyclyl-carbonyl,        heterocyclyl-carbonyl-oxy, C₃₋₁₄cycloalkyl,        aryl-C₁₋₈alkyl-amino, (aryl-C₁₋₈alkyl)₂-amino,        (aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        aryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (aryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        (aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, heteroaryl,        heteroaryl-C₁₋₈alkyl, heteroaryl-C₁₋₈alkoxy, heteroaryl-amino,        heteroaryl-C₁₋₈alkyl-amino, (heteroaryl-C₁₋₈alkyl)₂-amino,        (heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        heteroaryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (heteroaryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl or        (heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl; wherein, each        instance of heterocyclyl, C₃₋₁₄cycloalkyl, aryl and heteroaryl        is optionally substituted with R₃ and R₄ substituents; and,    -   wherein, heterocyclyl is selected from azetidinyl,        tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl,        1,4-diazepanyl, 1,2,5,6-tetrahydropyridinyl,        1,2,3,6-tetrahydropyridinyl,        hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl,        (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl,        (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl,        hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl,        (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl,        hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl,        (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl,        octahydro-5H-pyrrolo[3,2-c]pyridinyl,        octahydro-6H-pyrrolo[3,4-b]pyridinyl,        (4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridinyl,        (4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridinyl,        hexahydropyrrolo[1,2-a]pyrazin-(2H)-one,        hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl,        (7R,8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl,        (8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl,        (8aR)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl,        (8aS)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl,        (8aR)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl,        octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[3.1.0]hexyl,        (1R,5S)-3-azabicyclo[3.1.0]hexyl, 8-azabicyclo[3.2.1]octyl,        (1R,5S)-8-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]oct-2-enyl,        (1R,5S)-8-azabicyclo[3.2.1]oct-2-enyl, 9-azabicyclo[3.3.1]nonyl,        (1R,5S)-9-azabicyclo[3.3.1]nonyl, 2,5-diazabicyclo[2.2.1]heptyl,        (1S,4S)-2,5-diazabicyclo[2.2.1]heptyl,        2,5-diazabicyclo[2.2.2]octyl, 3,8-diazabicyclo[3.2.1]octyl,        (1R,5S)-3,8-diazabicyclo[3.2.1]octyl,        1,4-diazabicyclo[3.2.2]nonyl, azaspiro[3.3]heptyl,        2,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[3.5]nonyl,        5,8-diazaspiro[3.5]nonyl, 2,7-diazaspiro[4.4]nonyl or        6,9-diazaspiro[4.5]decyl.

In another embodiment of a compound of Formula (I),

-   -   R₂ is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl,        heteroaryl or heteroaryl-amino;    -   wherein, aryl is phenyl;    -   wherein, heterocyclyl is selected from        1,2,3,6-tetrahydropyridinyl, 1,3-benzodioxolyl or        2,3-dihydro-1,4-benzodioxinyl;    -   wherein, heteroaryl is selected from thienyl, 1H-pyrazolyl,        1H-imidazolyl, 1,3-thiazolyl, 1,2,4-oxadiazolyl,        1,3,4-oxadiazolyl, pyridinyl, pyrimidinyl, 1H-indolyl,        2H-indolyl, 1H-indazolyl, 2H-indazolyl, indolizinyl,        benzofuranyl, benzothienyl, 1H-benzimidazolyl,        1,3-benzothiazolyl, 1,3-benzoxazolyl, 9H-purinyl,        furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl,        furo[2,3-c]pyridinyl, thieno[3,2-c]pyridinyl,        thieno[2,3-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl,        1H-pyrrolo[2,3-c]pyridinyl, pyrrolo[1,2-a]pyrimidinyl,        pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-b]pyridazinyl,        pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrazinyl,        imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrimidinyl,        imidazo[1,2-c]pyrimidinyl, imidazo[1,2-b]pyridazinyl,        imidazo[1,2-a]pyrazinyl, imidazo[2,1-b][1,3]thiazolyl,        imidazo[2,1-b][1,3,4]thiadiazolyl, [1,3]oxazolo[4,5-b]pyridinyl        or quinoxalinyl; and, wherein, each instance of aryl,        heterocyclyl and heteroaryl is optionally substituted with R₆        and R₇ substituents.

In another embodiment of a compound of Formula (I),

-   -   R₁ is heterocyclyl, heterocyclyl-C₁₋₈alkyl,        heterocyclyl-C₁₋₈alkoxy, heterocyclyl-amino,        (heterocyclyl)(C₁₋₈alkyl)amino, heterocyclyl-amino-C₁₋₈alkyl,        heterocyclyl-C₁₋₈alkyl-amino, (heterocyclyl-C₁₋₈alkyl)₂-amino,        (heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        heterocyclyl-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (heterocyclyl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        (heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl,        heterocyclyl-oxy, heterocyclyl-carbonyl,        heterocyclyl-carbonyl-oxy, C₃₋₁₄cycloalkyl,        aryl-C₁₋₈alkyl-amino, (aryl-C₁₋₈alkyl)₂-amino,        (aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        aryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (aryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        (aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, heteroaryl,        heteroaryl-C₁₋₈alkyl, heteroaryl-C₁₋₈alkoxy, heteroaryl-amino,        heteroaryl-C₁₋₈alkyl-amino, (heteroaryl-C₁₋₈alkyl)₂-amino,        (heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        heteroaryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (heteroaryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl or        (heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl;    -   wherein, heterocyclyl is selected from azetidinyl,        tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl,        1,4-diazepanyl, 1,2,5,6-tetrahydropyridinyl,        1,2,3,6-tetrahydropyridinyl,        hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl,        (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl,        (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl,        hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl,        (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl,        hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl,        (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl,        octahydro-5H-pyrrolo[3,2-c]pyridinyl,        octahydro-6H-pyrrolo[3,4-b]pyridinyl,        (4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridinyl,        (4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridinyl,        hexahydropyrrolo[1,2-a]pyrazin-(2H)-one,        hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl,        (7R,8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl,        (8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl,        (8aR)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl,        (8aS)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl,        (8aR)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl,        octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[3.1.0]hexyl,        (1R,5S)-3-azabicyclo[3.1.0]hexyl, 8-azabicyclo[3.2.1]octyl,        (1R,5S)-8-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]oct-2-enyl,        (1R,5S)-8-azabicyclo[3.2.1]oct-2-enyl, 9-azabicyclo[3.3.1]nonyl,        (1R,5S)-9-azabicyclo[3.3.1]nonyl, 2,5-diazabicyclo[2.2.1]heptyl,        (1S,4S)-2,5-diazabicyclo[2.2.1]heptyl,        2,5-diazabicyclo[2.2.2]octyl, 3,8-diazabicyclo[3.2.1]octyl,        (1R,5S)-3,8-diazabicyclo[3.2.1]octyl,        1,4-diazabicyclo[3.2.2]nonyl, azaspiro[3.3]heptyl,        2,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[3.5]nonyl,        5,8-diazaspiro[3.5]nonyl, 2,7-diazaspiro[4.4]nonyl or        6,9-diazaspiro[4.5]decyl; and, wherein, each instance of        heterocyclyl, C₃₋₁₄cycloalkyl, aryl and heteroaryl is optionally        substituted with R₃ and R₄ substituents; and    -   R₂ is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl,        heteroaryl or heteroaryl-amino;    -   wherein, heterocyclyl is selected from        1,2,3,6-tetrahydropyridin-4-yl, 1,3-benzodioxol-5-yl or        2,3-dihydro-1,4-benzodioxin-6-yl;    -   wherein, heteroaryl is selected from thienyl, 1H-pyrazolyl,        1H-imidazolyl, 1,3-thiazolyl, 1,2,4-oxadiazolyl,        1,3,4-oxadiazolyl, pyridinyl, pyrimidinyl, 1H-indolyl,        2H-indolyl, 1H-indazolyl, 2H-indazolyl, indolizinyl,        benzofuranyl, benzothienyl, 1H-benzimidazolyl,        1,3-benzothiazolyl, 1,3-benzoxazolyl, 9H-purinyl,        furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl,        furo[2,3-c]pyridinyl, thieno[3,2-c]pyridinyl,        thieno[2,3-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl,        1H-pyrrolo[2,3-c]pyridinyl, pyrrolo[1,2-a]pyrimidinyl,        pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-b]pyridazinyl,        pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrazinyl,        imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrimidinyl,        imidazo[1,2-c]pyrimidinyl, imidazo[1,2-b]pyridazinyl,        imidazo[1,2-a]pyrazinyl, imidazo[2,1-b][1,3]thiazolyl,        imidazo[2,1-b][1,3,4]thiadiazolyl, [1,3]oxazolo[4,5-b]pyridinyl        or quinoxalinyl; and, wherein, each instance of heterocyclyl and        heteroaryl is optionally substituted with R₆ and R₇        substituents.

In another embodiment of a compound of Formula (I),

-   -   R₁ is C₁₋₈alkyl, amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino,        C₁₋₈alkoxy-C₁₋₈alkyl-amino, (C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino,        (C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino, amino-C₁₋₈alkyl,        C₁₋₈alkyl-amino-C₁₋₈alkyl, (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        (C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl,        amino-C₁₋₈alkyl-amino, (amino-C₁₋₈alkyl)₂-amino,        (amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        C₁₋₈alkyl-amino-C₁₋₈alkyl-amino,        (C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,        (C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,        [(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,        amino-C₁₋₈alkoxy, C₁₋₈alkyl-amino-C₁₋₈alkoxy,        (C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,        C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,        (C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,        (C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkoxy,        amino-C₂₋₈alkenyl, C₁₋₈alkyl-amino-C₂₋₈alkenyl,        (C₁₋₈alkyl)₂-amino-C₂₋₈alkenyl, amino-C₂₋₈alkynyl,        C₁₋₈alkyl-amino-C₂₋₈alkynyl, (C₁₋₈alkyl)₂-amino-C₂₋₈alkynyl,        halo-C₁₋₈alkyl-amino, (halo-C₁₋₈alkyl)₂-amino,        (halo-C₁₋₈alkyl)(C₁₋₈alkyl)amino, hydroxy-C₁₋₈alkyl,        hydroxy-C₁₋₈alkoxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkyl-amino,        (hydroxy-C₁₋₈alkyl)₂-amino, (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl,        hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,        (hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,        (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkoxy,        hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl-amino,        (hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,        (hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,        (hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl-amino,        [(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino or        [(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl](C₁₋₈alkyl)amino;        and    -   R₂ is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl,        heteroaryl or heteroaryl-amino, wherein, each instance of aryl,        heterocyclyl and heteroaryl is optionally substituted with R₆        and R₇ substituents.

In another embodiment of a compound of Formula (I),

-   -   R₁ is heterocyclyl, heterocyclyl-C₁₋₈alkyl,        heterocyclyl-C₁₋₈alkoxy, heterocyclyl-amino,        (heterocyclyl)(C₁₋₈alkyl)amino, heterocyclyl-amino-C₁₋₈alkyl,        heterocyclyl-C₁₋₈alkyl-amino, (heterocyclyl-C₁₋₈alkyl)₂-amino,        (heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        heterocyclyl-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (heterocyclyl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        (heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl,        heterocyclyl-oxy, heterocyclyl-carbonyl,        heterocyclyl-carbonyl-oxy, C₃₋₁₄cycloalkyl,        aryl-C₁₋₈alkyl-amino, (aryl-C₁₋₈alkyl)₂-amino,        (aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        aryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (aryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        (aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, heteroaryl,        heteroaryl-C₁₋₈alkyl, heteroaryl-C₁₋₈alkoxy, heteroaryl-amino,        heteroaryl-C₁₋₈alkyl-amino, (heteroaryl-C₁₋₈alkyl)₂-amino,        (heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        heteroaryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (heteroaryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl or        (heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl; wherein, each        instance of heterocyclyl, C₃₋₁₄cycloalkyl, aryl and heteroaryl        is optionally substituted with R₃ and R₄ substituents; and    -   R₂ is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl,        heteroaryl or heteroaryl-amino, wherein, each instance of aryl,        heterocyclyl and heteroaryl is optionally substituted with R₆        and R₇ substituents.

In another embodiment of a compound of Formula (I),

-   -   R₁ is heterocyclyl, heterocyclyl-C₁₋₈alkyl,        heterocyclyl-C₁₋₈alkoxy, heterocyclyl-amino,        (heterocyclyl)(C₁₋₈alkyl)amino, heterocyclyl-amino-C₁₋₈alkyl,        heterocyclyl-C₁₋₈alkyl-amino, (heterocyclyl-C₁₋₈alkyl)₂-amino,        (heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        heterocyclyl-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (heterocyclyl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        (heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl,        heterocyclyl-oxy, heterocyclyl-carbonyl or        heterocyclyl-carbonyl-oxy; wherein, each instance of        heterocyclyl is optionally substituted with R₃ and R₄        substituents; and    -   R₂ is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl,        heteroaryl or heteroaryl-amino, wherein, each instance of aryl,        heterocyclyl and heteroaryl is optionally substituted with R₆        and R₇ substituents.

In another embodiment of a compound of Formula (I),

-   -   R₁ is heterocyclyl optionally substituted with R₃ and R₄        substituents; and    -   R₂ is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl,        heteroaryl or heteroaryl-amino, wherein, each instance of aryl,        heterocyclyl and heteroaryl is optionally substituted with R₆        and R₇ substituents.

In another embodiment of a compound of Formula (I),

-   -   R₁ is C₃₋₁₄cycloalkyl optionally substituted with R₃ and R₄        substituents; and    -   R₂ is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl,        heteroaryl or heteroaryl-amino, wherein, each instance of aryl,        heterocyclyl and heteroaryl is optionally substituted with R₆        and R₇ substituents.

In another embodiment of a compound of Formula (I),

-   -   R₁ is aryl-C₁₋₈alkyl-amino, (aryl-C₁₋₈alkyl)₂-amino,        (aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        aryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (aryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl or        (aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl; wherein, each        instance of aryl is optionally substituted with R₃ and R₄        substituents; and    -   R₂ is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl,        heteroaryl or heteroaryl-amino, wherein, each instance of aryl,        heterocyclyl and heteroaryl is optionally substituted with R₆        and R₇ substituents.

In another embodiment of a compound of Formula (I),

-   -   R₁ is aryl-C₁₋₈alkyl-amino optionally substituted with R₃ and R₄        substituents; and    -   R₂ is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl,        heteroaryl or heteroaryl-amino, wherein, each instance of aryl,        heterocyclyl and heteroaryl is optionally substituted with R₆        and R₇ substituents.

In another embodiment of a compound of Formula (I),

-   -   R₁ is heteroaryl, heteroaryl-C₁₋₈alkyl, heteroaryl-C₁₋₈alkoxy,        heteroaryl-amino, heteroaryl-C₁₋₈alkyl-amino,        (heteroaryl-C₁₋₈alkyl)₂-amino,        (heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        heteroaryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (heteroaryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl or        (heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl; wherein, each        instance of heterocyclyl, C₃₋₁₄cycloalkyl, aryl and heteroaryl        is optionally substituted with R₃ and R₄ substituents; and    -   R₂ is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl,        heteroaryl or heteroaryl-amino, wherein, each instance of aryl,        heterocyclyl and heteroaryl is optionally substituted with R₆        and R₇ substituents.

In another embodiment of a compound of Formula (I),

-   -   R₁ is heteroaryl optionally substituted with R₃ and R₄        substituents; and    -   R₂ is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl,        heteroaryl or heteroaryl-amino, wherein, each instance of aryl,        heterocyclyl and heteroaryl is optionally substituted with R₆        and R₇ substituents.

An embodiment of the compound of Formula (I) is a compound selected fromFormula (II), Formula (III), Formula (IV), Formula (V), Formula (VI),Formula (VII), Formula (VIII), Formula (IX), Formula (X), Formula (XI),Formula (XII), Formula (XIII) or Formula (XIV):

or a form thereof.

In an embodiment of the compound of Formula (I), w₃ is C—R₁, w₆ is C—R₂,w₁, w₄, w₅ and w₁ are independently C—R_(a) or N and w₂ is C—R_(b) or N.

In another embodiment of the compound of Formula (I), w₃ is C—R₂, w₆ isC—R₁, w₁, w₄, w₅ and w₇ are independently C—R_(a) or N and w₂ is C—R_(b)or N.

In another embodiment of the compound of Formula (I), w₄ is C—R₁, w₇ isC—R₂, w₁, w₃ and w₅ are independently C—R_(a) or N, w₂ is C—R_(b) or Nand w₆ is C—R_(c) or N.

In another embodiment of the compound of Formula (I), w₄ is C—R₂, w₇ isC—R₁, w₁, w₃ and w₅ are independently C—R_(a) or N, w₂ is C—R_(b) or Nand w₆ is C—R_(c) or N.

In an embodiment of the compound of Formula (II), w₃ is C—R₁, w₆ isC—R₂, w₄, w₅ and w₇ are independently C—R_(a) or N and w₂ is C—R_(b) orN.

In another embodiment of the compound of Formula (II), w₃ is C—R₂, w₆ isC—R₁, w₄, w₅ and w₇ are independently C—R_(a) or N and w₂ is C—R_(b) orN.

In another embodiment of the compound of Formula (II), w₄ is C—R₁, w₇ isC—R₂, w₃ and w₅ are independently C—R_(a) or N, w₂ is C—R_(b) or N andw₆ is C—R_(c) or N.

In another embodiment of the compound of Formula (II), w₄ is C—R₂, w₇ isC—R₁, w₃ and w₅ are independently C—R_(a) or N, w₂ is C—R_(b) or N andw₆ is C—R_(c) or N.

In an embodiment of the compound of Formula (III), w₃ is C—R₁, w₆ isC—R₂ and w₁, w₄, w₅ and w₇ are independently C—R_(a) or N.

In another embodiment of the compound of Formula (III), w₃ is C—R₂, w₆is C—R₁ and w₁, w₄, w₅ and w₇ are independently C—R_(a) or N.

In another embodiment of the compound of Formula (III), w₄ is C—R₁, w₇is C—R₂, w₁, w₃ and w₅ are independently C—R_(a) or N and w₆ is C—R_(c)or N.

In another embodiment of the compound of Formula (III), w₄ is C—R₂, w₇is C—R₁, w₁, w₃ and w₅ are independently C—R_(a) or N and w₆ is C—R_(c)or N.

In an embodiment of the compound of Formula (IV), w₄ is C—R₁, w₇ isC—R₂, w₁ and w₅ are independently C—R_(a) or N, w₂ is C—R_(b) or N andw₆ is C—R_(c) or N.

In another embodiment of the compound of Formula (IV), w₄ is C—R₂, w₇ isC—R₁, w₁ and w₅ are independently C—R_(a) or N, w₂ is C—R_(b) or N andw₆ is C—R_(c) or N.

In an embodiment of the compound of Formula (V), w₃ is C—R₁, w₆ is C—R₂,w₁, w₅ and w₇ are independently C—R_(a) or N and w₂ is C—R_(b) or N.

In another embodiment of the compound of Formula (V), w₃ is C—R₂, w₆ isC—R₁, w₁, w₅ and w₇ are independently C—R_(a) or N and w₂ is C—R_(b) orN.

In an embodiment of the compound of Formula (VI), w₃ is C—R₁, w₆ isC—R₂, w₁, w₄ and w₇ are independently C—R_(a) or N and w₂ is C—R_(b) orN.

In another embodiment of the compound of Formula (VI), w₃ is C—R₂, w₆ isC—R₁, w₁, w₄ and w₇ are independently C—R_(a) or N and w₂ is C—R_(b) orN.

In another embodiment of the compound of Formula (VI), w₄ is C—R₁, w₇ isC—R₂, Wi and w₃ are independently C—R_(a) or N, w₂ is C—R_(b) or N andw₆ is C—R_(c) or N.

In another embodiment of the compound of Formula (VI), w₄ is C—R₂, w₇ isC—R₁, w₁ and w₃ are independently C—R_(a) or N, w₂ is C—R_(b) or N andw₆ is C—R_(c) or N.

In another embodiment of the compound of Formula (VII), w₄ is C—R₁, w₇is C—R₂, w₁, w₃ and w₅ are C—R_(a) or N and w₂ is C—R_(b) or N.

In another embodiment of the compound of Formula (VII), w₄ is C—R₂, w₇is C—R₁, w₁, w₃ and w₅ are C—R_(a) or N and w₂ is C—R_(b) or N.

In another embodiment of the compound of Formula (VIII), w₃ is C—R₁, w₆is C—R₂, w₁, w₄ and w₅ are C—R_(a) or N and w₂ is C—R_(b) or N.

In another embodiment of the compound of Formula (VIII), w₃ is C—R₂, w₆is C—R₁, w₁, w₄ and w₅ are C—R_(a) or N and w₂ is C—R_(b) or N.

In an embodiment of the compound of Formula (IX), w₃ is C—R₁, w₆ isC—R₂, w₄ and w₇ are independently C—R_(a) or N and w₂ is C—R_(b) or N.

In another embodiment of the compound of Formula (IX), w₃ is C—R₂, w₆ isC—R₁, w₄ and w₇ are independently C—R_(a) or N and w₂ is C—R_(b) or N.

In another embodiment of the compound of Formula (IX), w₄ is C—R₁, w₇ isC—R₂, w₂ is C—R_(b) or N, w₃ is C—R_(a) or N and w₆ is C—R_(c) or N.

In another embodiment of the compound of Formula (IX), w₄ is C—R₂, w₇ isC—R₁, w₂ is C—R_(b) or N, w₃ is C—R_(a) or N and w₆ is C—R_(c) or N.

In an embodiment of the compound of Formula (X), w₃ is C—R₁, w₆ is C—R₂,w₂ is C—R_(b) or N and w₅ and w₇ are independently C—R_(a) or N.

In another embodiment of the compound of Formula (X), w₃ is C—R₂, w₆ isC—R₁, w₂ is C—R_(b) or N and w₅ and w₇ are independently C—R_(a) or N.

In an embodiment of the compound of Formula (XI), w₄ is C—R₁, w₇ isC—R₂, w₂ is C—R_(b) or N, w₅ is C—R_(a) or N and w₆ is C—R_(c) or N.

In another embodiment of the compound of Formula (XI), w₄ is C—R₂, w₇ isC—R₁, w₂ is C—R_(b) or N, w₅ is C—R_(a) or N and w₆ is C—R_(c) or N.

In an embodiment of the compound of Formula (XII), w₃ is C—R₁, w₆ isC—R₂ and w₄, w₅ and w₇ are independently C—R_(a) or N.

In another embodiment of the compound of Formula (XII), w₃ is C—R₂, w₆is C—R₁ and w₄, w₅ and w₇ are independently C—R_(a) or N.

In another embodiment of the compound of Formula (XII), w₄ is C—R₁, w₇is C—R₂, w₃ and w₅ are independently C—R_(a) or N and w₆ is C—R_(c) orN.

In another embodiment of the compound of Formula (XII), w₄ is C—R₂, w₇is C—R₁, w₃ and w₅ are independently C—R_(a) or N and w₆ is C—R_(c) orN.

In an embodiment of the compound of Formula (XIII), w₃ is C—R₁, w₆ isC—R₂, w₂ is C—R_(b) or N and w₄ and w₅ are independently C—R_(a) or N.

In another embodiment of the compound of Formula (XIII), w₃ is C—R₂, w₆is C—R₁, w₂ is C—R_(b) or N and w₄ and w₅ are independently C—R_(a) orN.

In an embodiment of the compound of Formula (XIV), w₄ is C—R₁, w₇ isC—R₂, w₂ is C—R_(b) or N and w₃ and w₅ are independently C—R_(a) or N.

In another embodiment of the compound of Formula (XIV), w₄ is C—R₂, w₇is C—R₁, w₂ is C—R_(b) or N and w₃ and w₅ are independently C—R_(a) orN.

Another embodiment of the compound of Formula (I) is a compound selectedfrom Formula (II), Formula (III), Formula (IX), Formula (XI) or Formula(XII):

or a form thereof.

Another embodiment of the compound of Formula (I) is a compound ofFormula (II):

or a form thereof.

Another embodiment of the compound of Formula (I) is a compound ofFormula (III):

or a form thereof.

Another embodiment of the compound of Formula (I) is a compound ofFormula (IV):

or a form thereof.

Another embodiment of the compound of Formula (I) is a compound ofFormula (V):

or a form thereof.

Another embodiment of the compound of Formula (I) is a compound ofFormula (VI):

or a form thereof.

Another embodiment of the compound of Formula (I) is a compound ofFormula (VII):

or a form thereof.

Another embodiment of the compound of Formula (I) is a compound ofFormula (VIII):

or a form thereof.

Another embodiment of the compound of Formula (I) is a compound ofFormula (IX):

or a form thereof.

Another embodiment of the compound of Formula (I) is a compound ofFormula (X):

or a form thereof.

Another embodiment of the compound of Formula (I) is a compound ofFormula (XI):

or a form thereof.

Another embodiment of the compound of Formula (I) is a compound ofFormula (XII):

or a form thereof.

Another embodiment of the compound of Formula (I) is a compound ofFormula (XIII):

or a form thereof.

Another embodiment of the compound of Formula (I) is a compound ofFormula (XIV):

or a form thereof.

An embodiment of the compound of Formula (I), Formula (II), Formula(III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula(VIII), Formula (IX), Formula (X), Formula (XI), Formula (XII), Formula(XIII) or Formula (XIV) is a compound selected from Formula (Ia),Formula (IIa), Formula (IIIa), Formula (IVa), Formula (Va), Formula(VIa), Formula (VIIa), Formula (VIIIa), Formula (IXa), Formula (Xa),Formula (XIa), Formula (XIIa), Formula (XIIIa) or Formula (XIVa),respectively:

or a form thereof.

In an embodiment of the compound of Formula (Ia), one of w₃, w₄, w₆ andw₇ is C—R₁ and one other of w₃, w₄, w₆ and w₇ is C—R₂, provided that,

when w₃ is C—R₁, then w₆ is C—R₂ and w₄ and w₇ are independently C—R_(a)or N; or,

when w₃ is C—R₂, then w₆ is C—R₁ and w₄ and w₇ are independently C—R_(a)or N; or,

when w₄ is C—R₁, then w₇ is C—R₂ and w₃ is C—R_(a) or N and w₆ isC—R_(c) or N; or,

when w₄ is C—R₂, then w₇ is C—R₁ and w₃ is C—R_(a) or N and w₆ isC—R_(c) or N.

In an embodiment of the compound of Formula (IIa), one of w₃, w₄, w₆ andw₇ is C—R₁ and one other of w₃, w₄, w₆ and w₇ is C—R₂, provided that,

when w₃ is C—R₁, then w₆ is C—R₂ and w₄ and w₇ are independently C—R_(a)or N; or,

when w₃ is C—R₂, then w₆ is C—R₁ and w₄ and w₇ are independently C—R_(a)or N; or,

when w₄ is C—R₁, then w₇ is C—R₂ and w₃ is C—R_(a) or N and w₆ isC—R_(c) or N; or,

when w₄ is C—R₂, then w₇ is C—R₁ and w₃ is C—R_(a) or N and w₆ isC—R_(c) or N.

In an embodiment of the compound of Formula (IIIa), one of w₃, w₄, w₆and w₇ is C—R₁ and one other of w₃, w₄, w₆ and w₇ is C—R₂, providedthat,

when w₃ is C—R₁, then w₆ is C—R₂ and w₄ and w₇ are independently C—R_(a)or N; or,

when w₃ is C—R₂, then w₆ is C—R₁ and w₄ and w₇ are independently C—R_(a)or N; or,

when w₄ is C—R₁, then w₇ is C—R₂ and w₃ is C—R_(a) or N and w₆ isC—R_(c) or N; or,

when w₄ is C—R₂, then w₇ is C—R₁ and w₃ is C—R_(a) or N and w₆ isC—R_(c) or N.

In an embodiment of the compound of Formula (IVa), one of w₄ and w₇ isC—R₁ and the other is C—R₂, provided that, when w₄ is C—R₁, then w₇ isC—R₂; or, when w₄ is C—R₂, then w₇ is C—R₁.

In an embodiment of the compound of Formula (Va), one of w₃ and w₆ isC—R₁ and the other is C—R₂, provided that, when w₃ is C—R₁, then w₆ isC—R₂; or, when w₃ is C—R₂, then w₆ is C—R₁.

In an embodiment of the compound of Formula (VIa), one of w₃, w₄, w₆ andw₇ is C—R₁ and one other of w₃, w₄, w₆ and w₇ is C—R₂, provided that,

when w₃ is C—R₁, then w₆ is C—R₂ and w₄ and w₇ are independently C—R_(a)or N; or,

when w₃ is C—R₂, then w₆ is C—R₁ and w₄ and w₇ are independently C—R_(a)or N; or,

when w₄ is C—R₁, then w₇ is C—R₂ and w₃ is C—R_(a) or N and w₆ isC—R_(c) or N; or,

when w₄ is C—R₂, then w₇ is C—R₁ and w₃ is C—R_(a) or N and w₆ isC—R_(c) or N.

In an embodiment of the compound of Formula (VIIa), one of w₄ and w₇ isC—R₁ and the other is C—R₂, provided that, when w₄ is C—R₁, then w₇ isC—R₂; or, when w₄ is C—R₂, then w₇ is C—R₁.

In an embodiment of the compound of Formula (VIIIa), one of w₃ and w₆ isC—R₁ and the other is C—R₂, provided that, when w₃ is C—R₁, then w₆ isC—R₂; or, when w₃ is C—R₂, then w₆ is C—R₁.

In an embodiment of the compound of Formula (IXa), one of w₃, w₄, w₆ andw₇ is C—R₁ and one other of w₃, w₄, w₆ and w₇ is C—R₂, provided that,

when w₃ is C—R₁, then w₆ is C—R₂ and w₄ and w₇ are independently C—R_(a)or N; or,

when w₃ is C—R₂, then w₆ is C—R₁ and w₄ and w₇ are independently C—R_(a)or N; or,

when w₄ is C—R₁, then w₇ is C—R₂ and w₃ is C—R_(a) or N and w₆ isC—R_(c) or N; or,

when w₄ is C—R₂, then w₇ is C—R₁ and w₃ is C—R_(a) or N and w₆ isC—R_(c) or N.

In an embodiment of the compound of Formula (Xa), one of w₃ and w₆ isC—R₁ and the other is C—R₂, provided that, when w₃ is C—R₁, then w₆ isC—R₂; or, when w₃ is C—R₂, then w₆ is C—R₁.

In an embodiment of the compound of Formula (XIa), one of w₄ and w₇ isC—R₁ and the other is C—R₂, provided that, when w₄ is C—R₁, then w₇ isC—R₂; or, when w₄ is C—R₂, then w₇ is C—R₁.

In an embodiment of the compound of Formula (XIIa), one of w₃, w₄, w₆and w₇ is C—R₁ and one other of w₃, w₄, w₆ and w₇ is C—R₂, providedthat,

when w₃ is C—R₁, then w₆ is C—R₂ and w₄ and w₇ are independently C—R_(a)or N; or,

when w₃ is C—R₂, then w₆ is C—R₁ and w₄ and w₇ are independently C—R_(a)or N; or,

when w₄ is C—R₁, then w₇ is C—R₂ and w₃ is C—R_(a) or N and w₆ isC—R_(c) or N; or,

when w₄ is C—R₂, then w₇ is C—R₁ and w₃ is C—R_(a) or N and w₆ isC—R_(c) or N.

In an embodiment of the compound of Formula (XIIIa), one of w₃ and w₆ isC—R₁ and the other is C—R₂, provided that, when w₃ is C—R₁, then w₆ isC—R₂; or, when w₃ is C—R₂, then w₆ is C—R₁.

In an embodiment of the compound of Formula (XIVa), one of w₄ and w₇ isC—R₁ and the other is C—R₂, provided that, when w₄ is C—R₁, then w₇ isC—R₂; or, when w₄ is C—R₂, then w₇ is C—R₁.

An embodiment of the compound of Formula (I), Formula (II), Formula(III), Formula (IX), Formula (XI) or Formula (XII) is a compoundselected from Formula (Ia), Formula (IIa), Formula (IIIa), Formula(IXa), Formula (XIa) or Formula (XIIa), respectively:

or a form thereof.

Another embodiment of the compound of Formula (I) is a compound ofFormula (Ia):

or a form thereof.

Another embodiment of the compound of Formula (II) is a compound ofFormula (IIa):

or a form thereof.

Another embodiment of the compound of Formula (III) is a compound ofFormula (IIIa):

or a form thereof.

Another embodiment of the compound of Formula (IV) is a compound ofFormula (IVa):

or a form thereof.

Another embodiment of the compound of Formula (V) is a compound ofFormula (Va):

or a form thereof.

Another embodiment of the compound of Formula (VI) is a compound ofFormula (VIa):

or a form thereof.

Another embodiment of the compound of Formula (VII) is a compound ofFormula (VIIa):

or a form thereof.

Another embodiment of the compound of Formula (VIII) is a compound ofFormula (VIIIa):

or a form thereof.

Another embodiment of the compound of Formula (IX) is a compound ofFormula (IXa):

or a form thereof.

Another embodiment of the compound of Formula (X) is a compound ofFormula (Xa):

or a form thereof.

Another embodiment of the compound of Formula (XI) is a compound ofFormula (XIa):

or a form thereof.

Another embodiment of the compound of Formula (XII) is a compound ofFormula (XIIa):

or a form thereof.

Another embodiment of the compound of Formula (XIII) is a compound ofFormula (XIIIa):

or a form thereof.

Another embodiment of the compound of Formula (XIV) is a compound ofFormula (XIVa):

or a form thereof.

An embodiment of the compound of Formula (Ia) is a compound of Formula(Ia1), Formula (Ia2), Formula (Ia3) or Formula (Ia4):

or a form thereof.

An embodiment of the compound of Formula (IIa) is a compound of Formula(IIa1), Formula (IIa2), Formula (IIa3) or Formula (IIa4):

or a form thereof.

An embodiment of the compound of Formula (IIIa) is a compound of Formula(IIIa1), Formula (IIIa2), Formula (IIIa3) or Formula (IIIa4):

or a form thereof.

An embodiment of the compound of Formula (IVa) includes a compound ofFormula (IVa1) or Formula (IVa2):

or a form thereof.

An embodiment of the compound of Formula (Va) is a compound of Formula(Va1) or Formula (Va2):

or a form thereof.

An embodiment of the compound of Formula (VIa) is a compound of Formula(VIa1), Formula (VIa2), Formula (VIa3) or Formula (VIa4):

or a form thereof.

An embodiment of the compound of Formula (VIIa) includes a compound ofFormula (VIIa1) or Formula (VIIa2):

or a form thereof.

An embodiment of the compound of Formula (VIIIa) is a compound ofFormula (VIIIa1) or Formula (VIIIa2):

or a form thereof.

An embodiment of the compound of Formula (IXa) is a compound of Formula(IXa1), Formula (IXa2), Formula (IXa3) or Formula (IXa4):

or a form thereof.

An embodiment of the compound of Formula (Xa) is a compound of Formula(Xa1) or Formula (Xa2):

or a form thereof.

An embodiment of the compound of Formula (XIa) is a compound of Formula(XIa1) or Formula (XIa2):

or a form thereof.

An embodiment of the compound of Formula (XIIa) is a compound of Formula(XIIa1), Formula (XIIa2), Formula (XIIa3) or Formula (XIIa4):

or a form thereof.

An embodiment of the compound of Formula (XIIIa) is a compound ofFormula (XIIIa1) or Formula (XIIIa2):

or a form thereof.

An embodiment of the compound of Formula (XIVa) is a compound of Formula(XIVa1) or Formula (XIVa2):

or a form thereof.

An embodiment of the compound of Formula (Ia) is a compound of Formula(Ia1):

or a form thereof.

An embodiment of the compound of Formula (Ia) is a compound of Formula(Ia2):

or a form thereof.

An embodiment of the compound of Formula (Ia) is a compound of Formula(Ia3):

or a form thereof.

An embodiment of the compound of Formula (Ia) is a compound of Formula(Ia4):

or a form thereof.

An embodiment of the compound of Formula (IIa) is a compound of Formula(IIa1):

or a form thereof.

An embodiment of the compound of Formula (IIa) is a compound of Formula(IIa2):

or a form thereof.

An embodiment of the compound of Formula (IIa) is a compound of Formula(IIa3):

or a form thereof.

An embodiment of the compound of Formula (IIa) is a compound of Formula(IIa4):

or a form thereof.

An embodiment of the compound of Formula (IIIa) is a compound of Formula(IIIa1):

or a form thereof.

An embodiment of the compound of Formula (IIIa) is a compound of Formula(IIIa2):

or a form thereof.

An embodiment of the compound of Formula (IIIa) is a compound of Formula(IIIa3):

or a form thereof.

An embodiment of the compound of Formula (IIIa) is a compound of Formula(IIIa4):

or a form thereof.

An embodiment of the compound of Formula (IVa) is a compound of Formula(IVa1):

or a form thereof.

An embodiment of the compound of Formula (IVa) is a compound of Formula(IVa2):

or a form thereof.

An embodiment of the compound of Formula (Va) is a compound of Formula(Va1):

or a form thereof.

An embodiment of the compound of Formula (Va) is a compound of Formula(Va2):

or a form thereof.

An embodiment of the compound of Formula (VIa) is a compound of Formula(VIa1):

or a form thereof.

An embodiment of the compound of Formula (VIa) is a compound of Formula(VIa2):

or a form thereof.

An embodiment of the compound of Formula (VIa) is a compound of FormulaFormula (VIa3):

or a form thereof.

An embodiment of the compound of Formula (VIa) is a compound of Formula(VIa4):

or a form thereof.

An embodiment of the compound of Formula (VIIa) is a compound of Formula(VIIa1):

or a form thereof.

An embodiment of the compound of Formula (VIIa) is a compound of Formula(VIIa2):

or a form thereof.

An embodiment of the compound of Formula (VIIIa) is a compound ofFormula (VIIIa1):

or a form thereof.

An embodiment of the compound of Formula (VIIIa) is a compound ofFormula (VIIIa2):

or a form thereof.

An embodiment of the compound of Formula (IXa) is a compound of Formula(IXa1):

or a form thereof.

An embodiment of the compound of Formula (IXa) is a compound of Formula(IXa2):

or a form thereof.

An embodiment of the compound of Formula (IXa) is a compound of Formula(IXa3):

or a form thereof.

An embodiment of the compound of Formula (IXa) is a compound of Formula(IXa4):

or a form thereof.

An embodiment of the compound of Formula (Xa) is a compound of Formula(Xa1):

or a form thereof.

An embodiment of the compound of Formula (Xa) is a compound of Formula(Xa2):

or a form thereof.

An embodiment of the compound of Formula (XIa) is a compound of Formula(XIa1):

or a form thereof.

An embodiment of the compound of Formula (XIa) is a compound of Formula(XIa2):

or a form thereof.

An embodiment of the compound of Formula (XIIa) is a compound of Formula(XIIa1):

or a form thereof.

An embodiment of the compound of Formula (XIIa) is a compound of Formula(XIIa2):

or a form thereof.

An embodiment of the compound of Formula (XIIa) is a compound of Formula(XIIa3):

or a form thereof.

An embodiment of the compound of Formula (XIIa) is a compound of Formula(XIIa4):

or a form thereof.

An embodiment of the compound of Formula (XIIIa) is a compound ofFormula (XIIIa1):

or a form thereof.

An embodiment of the compound of Formula (XIIIa) is a compound ofFormula (XIIIa2):

or a form thereof.

An embodiment of the compound of Formula (XIVa) is a compound of Formula(XIVa):

or a form thereof.

An embodiment of the compound of Formula (XIVa) is a compound of Formula(XIVa2):

or a form thereof.

An embodiment of the compound of Formula (I) is a compound selected fromthe group consisting of:

or a form thereof.

Terminology

The chemical terms used above and throughout the description herein,unless specifically defined otherwise, shall be understood by one ofordinary skill in the art to have the following indicated meanings.

As used herein, the term “C₁₋₈alkyl” generally refers to saturatedhydrocarbon radicals having from one to eight carbon atoms in a straightor branched chain configuration, including, but not limited to, methyl,ethyl, n-propyl (also referred to as propyl or propanyl), isopropyl,n-butyl (also referred to as butyl or butanyl), isobutyl, sec-butyl,tert-butyl, n-pentyl (also referred to as pentyl or pentanyl), n-hexyl(also referred to as hexyl or hexanyl), n-heptyl (also referred to asheptyl or heptanyl), n-octyl and the like. In some embodiments,C₁₋₈alkyl includes, but is not limited to, C₁₋₆alkyl, C₁₋₄alkyl and thelike. A C₁₋₈alkyl radical is optionally substituted with substituentspecies as described herein where allowed by available valences.

As used herein, the term “C₂₋₈alkenyl” generally refers to partiallyunsaturated hydrocarbon radicals having from two to eight carbon atomsin a straight or branched chain configuration and one or morecarbon-carbon double bonds therein, including, but not limited to,ethenyl (also referred to as vinyl), allyl, propenyl and the like. Insome embodiments, C₂₋₈alkenyl includes, but is not limited to,C₂₋₆alkenyl, C₂₋₄alkenyl and the like. A C₂₋₈alkenyl radical isoptionally substituted with substituent species as described hereinwhere allowed by available valences.

As used herein, the term “C₂₋₈alkynyl” generally refers to partiallyunsaturated hydrocarbon radicals having from two to eight carbon atomsin a straight or branched chain configuration and one or morecarbon-carbon triple bonds therein, including, but not limited to,ethynyl, propynyl, butynyl and the like. In some embodiments,C₂₋₈alkynyl includes, but is not limited to, C₂₋₆alkynyl, C₂₋₄alkynyland the like. A C₂₋₈alkynyl radical is optionally substituted withsubstituent species as described herein where allowed by availablevalences.

As used herein, the term “C₁₋₈alkoxy” generally refers to saturatedhydrocarbon radicals having from one to eight carbon atoms in a straightor branched chain configuration of the formula: —O—C₁₋₈alkyl, including,but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy and the like. Insome embodiments, C₁₋₈alkoxy includes, but is not limited to,C₁₋₆alkoxy, C₁₋₄alkoxy and the like. A C₁₋₈alkoxy radical is optionallysubstituted with substituent species as described herein where allowedby available valences.

As used herein, the term “C₃₋₁₄cycloalkyl” generally refers to asaturated or partially unsaturated monocyclic, bicyclic or polycyclichydrocarbon radical, including, but not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl,cyclooctyl, 1H-indanyl, indenyl, tetrahydro-naphthalenyl and the like.In some embodiments, C₃₋₁₄cycloalkyl includes, but is not limited to,C₃₋₈cycloalkyl, C₅₋₈cycloalkyl, C₃₋₁₀cycloalkyl and the like. AC₃₋₁₄cycloalkyl radical is optionally substituted with substituentspecies as described herein where allowed by available valences.

As used herein, the term “aryl” generally refers to a monocyclic,bicyclic or polycyclic aromatic carbon atom ring structure radical,including, but not limited to, phenyl, naphthyl, anthracenyl, fluorenyl,azulenyl, phenanthrenyl and the like. An aryl radical is optionallysubstituted with substituent species as described herein where allowedby available valences.

As used herein, the term “heteroaryl” generally refers to a monocyclic,bicyclic or polycyclic aromatic carbon atom ring structure radical inwhich one or more carbon atom ring members have been replaced, whereallowed by structural stability, with one or more heteroatoms, such asan O, S or N atom, including, but not limited to, furanyl (also referredto as furyl), thienyl (also referred to as thiophenyl), pyrrolyl,2H-pyrrolyl, 3H-pyrrolyl, pyrazolyl, 1H-pyrazolyl, imidazolyl,1H-imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, 1,3-thiazolyl,triazolyl (such as 1H-1,2,3-triazolyl and the like), oxadiazolyl (suchas 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl and the like), thiadiazolyl,tetrazolyl (such as 1H-tetrazolyl, 2H-tetrazolyl and the like),pyridinyl (also referred to as pyridyl), pyrimidinyl, pyrazinyl,pyridazinyl, triazinyl, indolyl, 1H-indolyl, indazolyl, 1H-indazolyl,2H-indazolyl, indolizinyl, isoindolyl, benzofuranyl, benzothienyl (alsoreferred to as benzothiophenyl), benzoimidazolyl, 1H-benzoimidazolyl,1,3-benzothiazolyl, 1,3-benzoxazolyl (also referred to as1,3-benzooxazolyl), purinyl, 9H-purinyl, quinolinyl, isoquinolinyl,quinazolinyl, quinoxalinyl, 1,3-diazinyl, 1,2-diazinyl, 1,2-diazolyl,1,4-diazanaphthalenyl, acridinyl, furo[3,2-b]pyridinyl,furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 6H-thieno[2,3-b]pyrrolyl,thieno[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl,1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl,1H-pyrrolo[3,2-b]pyridinyl, pyrrolo[1,2-a]pyrazinyl,pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridinyl,pyrazolo[1,5-a]pyrazinyl, imidazo[1,2-a]pyridinyl,3H-imidazo[4,5-b]pyridinyl, imidazo[1,2-a]pyrimidinyl,imidazo[1,2-c]pyrimidinyl, imidazo[1,2-b]pyridazinyl,imidazo[1,2-a]pyrazinyl, imidazo[2,1-b][1,3]thiazolyl,imidazo[2,1-b][1,3,4]thiadiazolyl, [1,2,4]triazolo[1,5-a]pyridinyl,[1,2,4]triazolo[4,3-a]pyridinyl and the like. A heteroaryl radical isoptionally substituted on a carbon or nitrogen atom ring member withsubstituent species as described herein where allowed by availablevalences.

As used herein, the term “heterocyclyl” generally refers to a saturatedor partially unsaturated monocyclic, bicyclic or polycyclic carbon atomring structure radical in which one or more carbon atom ring membershave been replaced, where allowed by structural stability, with aheteroatom, such as an O, S or N atom, including, but not limited to,oxiranyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolinyl,pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,isoxazolinyl, isoxazolidinyl, isothiazolinyl, isothiazolidinyl,oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, triazolinyl,triazolidinyl, oxadiazolinyl, oxadiazolidinyl, thiadiazolinyl,thiadiazolidinyl, tetrazolinyl, tetrazolidinyl, pyranyl,dihydro-2H-pyranyl, thiopyranyl, 1,3-dioxanyl,1,2,5,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, 1,4-diazepanyl,1,3-benzodioxolyl (also referred to as benzo[d][1,3]dioxolyl),1,4-benzodioxanyl, 2,3-dihydro-1,4-benzodioxinyl (also referred to as2,3-dihydrobenzo[b][1,4]dioxinyl),hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl,(3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl,(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl,hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl,(3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl,(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl,hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl,(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl,(3aR,6aR)-hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl,octahydro-5H-pyrrolo[3,2-c]pyridinyl,octahydro-6H-pyrrolo[3,4-b]pyridinyl,(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridinyl,(4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridinyl,hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl,(7R,8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl,(8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl,(8aR)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl,(8aS)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl,(8aR)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl,hexahydropyrrolo[1,2-a]pyrazin-(2H)-one,octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[3.1.0]hexyl,(1R,5S)-3-azabicyclo[3.1.0]hexyl, 8-azabicyclo[3.2.1]octyl,(1R,5S)-8-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]oct-2-enyl,(1R,5S)-8-azabicyclo[3.2.1]oct-2-enyl, 9-azabicyclo[3.3.1]nonyl,(1R,5S)-9-azabicyclo[3.3.1]nonyl, 2,5-diazabicyclo[2.2.1]heptyl,(1S,4S)-2,5-diazabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl,3,8-diazabicyclo[3.2.1]octyl, (1R,5S)-3,8-diazabicyclo[3.2.1]octyl,1,4-diazabicyclo[3.2.2]nonyl, azaspiro[3.3]heptyl,2,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[3.5]nonyl,5,8-diazaspiro[3.5]nonyl, 2,7-diazaspiro[4.4]nonyl,6,9-diazaspiro[4.5]decyl and the like. A heterocyclyl radical isoptionally substituted on a carbon or nitrogen atom ring member withsubstituent species as described herein where allowed by availablevalences.

As used herein, the term “C₁₋₈alkoxy-C₁₋₈alkyl” refers to a radical ofthe formula: —C₁₋₈alkyl-O—C₁₋₈alkyl.

As used herein, the term “C₁₋₈alkoxy-C₁₋₈alkyl-amino” refers to aradical of the formula: —NH—C₁₋₈alkyl-O—C₁₋₈alkyl.

As used herein, the term “(C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino” refers to aradical of the formula: —N(C₁₋₈alkyl-O—C₁₋₈alkyl)₂.

As used herein, the term “C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy” refersto a radical of the formula: —O—C₁₋₈alkyl-NH—C₁₋₈alkyl-O—C₁₋₈alkyl.

As used herein, the term “(C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy”refers to a radical of the formula:—O—C₁₋₈alkyl-N(C₁₋₈alkyl-O—C₁₋₈alkyl)₂.

As used herein, the term“(C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkoxy” refers to a radicalof the formula: —O—C₁₋₈alkyl-N(C₁₋₈alkyl)(C₁₋₈alkyl-O—C₁₋₈alkyl).

As used herein, the term “C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkyl” refersto a radical of the formula: —C₁₋₈alkyl-NH—C₁₋₈alkyl-O—C₁₋₈alkyl.

As used herein, the term “(C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl”refers to a radical of the formula:—C₁₋₈alkyl-N(C₁₋₈alkyl-O—C₁₋₈alkyl)₂.

As used herein, the term“(C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl” refers to a radicalof the formula: —C₁₋₈alkyl-N(C₁₋₈alkyl)(C₁₋₈alkyl-O—C₁₋₈alkyl).

As used herein, the term “C₁₋₈alkoxy-carbonyl” refers to a radical ofthe formula: —C(O)—O—C₁₋₈alkyl.

As used herein, the term “C₁₋₈alkoxy-carbonyl-C₂₋₈alkenyl” refers to aradical of the formula: —C₂₋₈alkenyl-C(O)—O—C₁₋₈alkyl.

As used herein, the term “C₁₋₈alkoxy-carbonyl-amino” refers to a radicalof the formula: —NH—C(O)—O—C₁₋₈alkyl.

As used herein, the term “C₁₋₈alkyl-amino” refers to a radical of theformula: —NH—C₁₋₈alkyl.

As used herein, the term “(C₁₋₈alkyl)₂-amino” refers to a radical of theformula: —N(C₁₋₈alkyl)₂.

As used herein, the term “C₁₋₈alkyl-amino-C₂₋₈alkenyl” refers to aradical of the formula: —C₂₋₈alkenyl-NH—C₁₋₈alkyl.

As used herein, the term “(C₁₋₈alkyl)₂-amino-C₂₋₈alkenyl” refers to aradical of the formula: —C₂₋₈alkenyl-N(C₁₋₈alkyl)₂.

As used herein, the term “C₁₋₈alkyl-amino-C₁₋₈alkoxy” refers to aradical of the formula: —O—C₁₋₈alkyl-NH—C₁₋₈alkyl.

As used herein, the term “(C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy” refers to aradical of the formula: —O—C₁₋₈alkyl-N(C₁₋₈alkyl)₂.

As used herein, the term “C₁₋₈alkyl-amino-C₁₋₈alkyl” refers to a radicalof the formula: —C₁₋₈alkyl-NH—C₁₋₈alkyl.

As used herein, the term “(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl” refers to aradical of the formula: —C₁₋₈alkyl-N(C₁₋₈alkyl)₂.

As used herein, the term “C₁₋₈alkyl-amino-C₁₋₈alkyl-amino” refers to aradical of the formula: —NH—C₁₋₈alkyl-NH—C₁₋₈alkyl.

As used herein, the term “(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino” refers toa radical of the formula: —NH—C₁₋₈alkyl-N(C₁₋₈alkyl)₂.

As used herein, the term “(C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino” refers toa radical of the formula: —N(C₁₋₈alkyl-NH—C₁₋₈alkyl)₂.

As used herein, the term “[(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl]₂-amino” refersto a radical of the formula: —N[C₁₋₈alkyl-N(C₁₋₈alkyl)₂]₂.

As used herein, the term “(C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino”refers to a radical of the formula:—N(C₁₋₈alkyl)(C₁₋₈alkyl-NH—C₁₋₈alkyl).

As used herein, the term“[(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino” refers to a radical ofthe formula: —N(C₁₋₈alkyl)[C₁₋₈alkyl-N(C₁₋₈alkyl)_(2].)

As used herein, the term “C₁₋₈alkyl-amino-C₂₋₈alkynyl” refers to aradical of the formula: —C₂₋₈alkynyl-NH—C₁₋₈alkyl.

As used herein, the term “(C₁₋₈alkyl)₂-amino-C₂₋₈alkynyl” refers to aradical of the formula: —C₂₋₈alkynyl-N(C₁₋₈alkyl)₂.

As used herein, the term “C₁₋₈alkyl-carbonyl” refers to a radical of theformula: —C(O)—C₁₋₈alkyl.

As used herein, the term “C₁₋₈alkyl-carbonyl-amino” refers to a radicalof the formula: —NH—C(O)—C₁₋₈alkyl.

As used herein, the term “C₁₋₈alkyl-thio” refers to a radical of theformula: —S—C₁₋₈alkyl.

As used herein, the term “amino-C₂₋₈alkenyl” refers to a radical of theformula: —C₂₋₈alkenyl-NH₂.

As used herein, the term “amino-C₁₋₈alkoxy” refers to a radical of theformula: —O—C₁₋₈alkyl-NH₂.

As used herein, the term “amino-C₁₋₈alkyl” refers to a radical of theformula: —C₁₋₈alkyl-NH₂.

As used herein, the term “amino-C₁₋₈alkyl-amino” refers to a radical ofthe formula: —NH—C₁₋₈alkyl-NH₂.

As used herein, the term “(amino-C₁₋₈alkyl)₂-amino” refers to a radicalof the formula: —N(C₁₋₈alkyl-NH₂)₂.

As used herein, the term “(amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino” refers to aradical of the formula: —N(C₁₋₈alkyl)(C₁₋₈alkyl-NH₂).

As used herein, the term “amino-C₂₋₈alkynyl” refers to a radical of theformula: —C₂₋₈alkynyl-NH₂.

As used herein, the term “aryl-C₁₋₈alkoxy-carbonyl” refers to a radicalof the formula: —C(O)—O—C₁₋₈alkyl-aryl.

As used herein, the term “aryl-C₁₋₈alkyl” refers to a radical of theformula: —C₁₋₈alkyl-aryl.

As used herein, the term “aryl-C₁₋₈alkyl-amino” refers to a radical ofthe formula: —NH—C₁₋₈alkyl-aryl.

As used herein, the term “(aryl-C₁₋₈alkyl)₂-amino” refers to a radicalof the formula: —N(C₁₋₈alkyl-aryl)₂.

As used herein, the term “(aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino” refers to aradical of the formula: —N(C₁₋₈alkyl)(C₁₋₈alkyl-aryl).

As used herein, the term “aryl-C₁₋₈alkyl-amino-C₁₋₈alkyl” refers to aradical of the formula: —C₁₋₈alkyl-NH—C₁₋₈alkyl-aryl.

As used herein, the term “(aryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl” refers to aradical of the formula: —C₁₋₈alkyl-N(C₁₋₈alkyl-aryl)₂.

As used herein, the term “(aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl”refers to a radical of the formula:—C₁₋₈alkyl-N(C₁₋₈alkyl)(C₁₋₈alkyl-aryl).

As used herein, the term “aryl-amino” refers to a radical of theformula: —NH-aryl.

As used herein, the term “aryl-amino-carbonyl” refers to a radical ofthe formula: —C(O)—NH-aryl.

As used herein, the term “aryl-sulfonyloxy-C₁₋₈alkyl” refers to aradical of the formula: —C₁₋₈alkyl-O—SO₂-aryl.

As used herein, the term “benzoxy-carbonyl” refers to a radical of theformula: —C(O)—O—CH₂-phenyl.

As used herein, the term “C₃₋₁₄cycloalkyl-C₁₋₈alkyl” refers to a radicalof the formula: —C₁₋₈alkyl-C₃₋₁₄cycloalkyl.

As used herein, the term “C₃₋₁₄cycloalkyl-amino” refers to a radical ofthe formula: —NH—C₃₋₁₄cycloalkyl.

As used herein, the term “C₃₋₁₄cycloalkyl-oxy” refers to a radical ofthe formula: —O—C₃₋₁₄cycloalkyl.

As used herein, the term “halo” or “halogen” generally refers to ahalogen atom radical, including fluoro, chloro, bromo and iodo.

As used herein, the term “halo-C₁₋₈alkoxy” refers to a radical of theformula: —O—C₁₋₈alkyl-halo, wherein C₁₋₈alkyl is partially or completelysubstituted with one or more halogen atoms where allowed by availablevalences.

As used herein, the term “halo-C₁₋₈alkyl” refers to a radical of theformula: —C₁₋₈alkyl-halo, wherein C₁₋₈alkyl is partially or completelysubstituted with one or more halogen atoms where allowed by availablevalences.

As used herein, the term “halo-C₁₋₈alkyl-amino” refers to a radical ofthe formula: —NH—C₁₋₈alkyl-halo.

As used herein, the term “(halo-C₁₋₈alkyl)(C₁₋₈alkyl)amino” refers to aradical of the formula: —N(C₁₋₈alkyl)(C₁₋₈alkyl-halo).

As used herein, the term “(halo-C₁₋₈alkyl)₂-amino” refers to a radicalof the formula: —N(C₁₋₈alkyl-halo)₂.

As used herein, the term “heteroaryl-C₁₋₈alkoxy” refers to a radical ofthe formula: —O—C₁₋₈alkyl-heteroaryl.

As used herein, the term “heteroaryl-C₁₋₈alkyl” refers to a radical ofthe formula: —C₁₋₈alkyl-heteroaryl.

As used herein, the term “heteroaryl-C₁₋₈alkyl-amino” refers to aradical of the formula: —NH—C₁₋₈alkyl-heteroaryl.

As used herein, the term “(heteroaryl-C₁₋₈alkyl)₂-amino” refers to aradical of the formula: —N(C₁₋₈alkyl-heteroaryl)₂.

As used herein, the term “(heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino” refersto a radical of the formula: —N(C₁₋₈alkyl)(C₁₋₈alkyl-heteroaryl).

As used herein, the term “heteroaryl-C₁₋₈alkyl-amino-C₁₋₈alkyl” refersto a radical of the formula: —C₁₋₈alkyl-NH—C₁₋₈alkyl-heteroaryl.

As used herein, the term “(heteroaryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl”refers to a radical of the formula: —C₁₋₈alkyl-N(C₁₋₈alkyl-heteroaryl)₂.

As used herein, the term“(heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl” refers to a radicalof the formula: —C₁₋₈alkyl-N(C₁₋₈alkyl)(C₁₋₈alkyl-heteroaryl).

As used herein, the term “heteroaryl-amino” refers to a radical of theformula: —NH-heteroaryl.

As used herein, the term “heterocyclyl-C₁₋₈alkoxy” refers to a radicalof the formula: —O—C₁₋₈alkyl-heterocyclyl.

As used herein, the term “heterocyclyl-C₁₋₈alkyl” refers to a radical ofthe formula: —C₁₋₈alkyl-heterocyclyl.

As used herein, the term “heterocyclyl-C₁₋₈alkyl-amino” refers to aradical of the formula: —NH—C₁₋₈alkyl-heterocyclyl.

As used herein, the term “(heterocyclyl-C₁₋₈alkyl)₂-amino” refers to aradical of the formula: —N(C₁₋₈alkyl-heterocyclyl)₂.

As used herein, the term “(heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino”refers to a radical of the formula:—N(C₁₋₈alkyl)(C₁₋₈alkyl-heterocyclyl).

As used herein, the term “heterocyclyl-C₁₋₈alkyl-amino-C₁₋₈alkyl” refersto a radical of the formula: —C₁₋₈alkyl-NH—C₁₋₈alkyl-heterocyclyl.

As used herein, the term “(heterocyclyl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl”refers to a radical of the formula:—C₁₋₈alkyl-N(C₁₋₈alkyl-heterocyclyl)₂.

As used herein, the term“(heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl” refers to a radicalof the formula: —C₁₋₈alkyl-N(C₁₋₈alkyl)(C₁₋₈alkyl-heterocyclyl).

As used herein, the term “heterocyclyl-amino” refers to a radical of theformula: —NH-heterocyclyl.

As used herein, the term “(heterocyclyl)(C₁₋₈alkyl)amino” refers to aradical of the formula: —N(C₁₋₈alkyl)(heterocyclyl).

As used herein, the term “heterocyclyl-amino-C₁₋₈alkyl” refers to aradical of the formula: —C₁₋₈alkyl-NH-heterocyclyl.

As used herein, the term “heterocyclyl-carbonyl” refers to a radical ofthe formula: —C(O)-heterocyclyl.

As used herein, the term “heterocyclyl-carbonyl-oxy” refers to a radicalof the formula: —O—C(O)-heterocyclyl.

As used herein, the term “heterocyclyl-oxy” refers to a radical of theformula: —O-heterocyclyl.

As used herein, the term “hydroxy” refers to a radical of the formula:—OH.

As used herein, the term “hydroxy-C₁₋₈alkoxy-C₁₋₈alkyl” refers to aradical of the formula: —C₁₋₈alkyl-O—C₁₋₈alkyl-OH.

As used herein, the term “hydroxy-C₁₋₈alkyl” refers to a radical of theformula: —C₁₋₈alkyl-OH, wherein C₁₋₈alkyl is partially or completelysubstituted with one or more hydroxy radicals where allowed by availablevalences.

As used herein, the term “hydroxy-C₁₋₈alkyl-amino” refers to a radicalof the formula: —NH—C₁₋₈alkyl-OH.

As used herein, the term “(hydroxy-C₁₋₈alkyl)₂-amino” refers to aradical of the formula: —N(C₁₋₈alkyl-OH)₂.

As used herein, the term “(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino” refers toa radical of the formula: —N(C₁₋₈alkyl)(C₁₋₈alkyl-OH).

As used herein, the term “hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl” refers to aradical of the formula: —C₁₋₈alkyl-NH—C₁₋₈alkyl-OH.

As used herein, the term “(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl” refersto a radical of the formula: —C₁₋₈alkyl-N(C₁₋₈alkyl-OH)₂.

As used herein, the term “(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl”refers to a radical of the formula:—C₁₋₈alkyl-N(C₁₋₈alkyl)(C₁₋₈alkyl-OH).

As used herein, the term “hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy” refers toa radical of the formula: —O—C₁₋₈alkyl-NH—C₁₋₈alkyl-OH.

As used herein, the term “(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy” refersto a radical of the formula: —O—C₁₋₈alkyl-N(C₁₋₈alkyl-OH)₂.

As used herein, the term“(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkoxy” refers to a radical ofthe formula: —O—C₁₋₈alkyl-N(C₁₋₈alkyl)(C₁₋₈alkyl-OH).

As used herein, the term “hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl-amino”refers to a radical of the formula: —NH—C₁₋₈alkyl-NH—C₁₋₈alkyl-OH.

As used herein, the term “(hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino”refers to a radical of the formula: —N(C₁₋₈alkyl-NH—C₁₋₈alkyl-OH)₂.

As used herein, the term “(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino”refers to a radical of the formula: —NH—C₁₋₈alkyl-N(C₁₋₈alkyl-OH)₂.

As used herein, the term“(hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino” refers to aradical of the formula: —N(C₁₋₈alkyl)(C₁₋₈alkyl-NH—C₁₋₈alkyl-OH).

As used herein, the term“[(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino” refers to aradical of the formula: —N(C₁₋₈alkyl)[C₁₋₈alkyl-N(C₁₋₈alkyl-OH)₂].

As used herein, the term“(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl-amino” refers to aradical of the formula: —NH—C₁₋₈alkyl-N(C₁₋₈alkyl, C₁₋₈alkyl-OH).

As used herein, the term“[(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl](C₁₋₈alkyl)amino” refersto a radical of the formula:—N(C₁₋₈alkyl)[C₁₋₈alkyl-N(C₁₋₈alkyl)(C₁₋₈alkyl-OH)].

As used herein, the term “substituent” means positional variables on theatoms of a core molecule that are attached at a designated atomposition, replacing one or more hydrogen atoms on the designated atom,provided that the atom of attachment does not exceed the availablevalence or shared valences, such that the substitution results in astable compound. Accordingly, combinations of substituents and/orvariables are permissible only if such combinations result in stablecompounds. It should also be noted that any carbon as well as heteroatomwith a valence level that appears to be unsatisfied as described orshown herein is assumed to have a sufficient number of hydrogen atom(s)to satisfy the valences described or shown.

For the purposes of this description, where one or more substituentvariables for a compound of Formula (I) encompass functionalitiesincorporated into a compound of Formula (I), each functionalityappearing at any location within the disclosed compound may beindependently selected, and as appropriate, independently and/oroptionally substituted.

As used herein, the terms “independently selected,” or “each selected”refer to functional variables in a substituent list that may be attachedmore than once on the structure of a core molecule, where the pattern ofsubstitution at each occurrence is independent of the pattern at anyother occurrence. Further, the use of a generic substituent on a corestructure for a compound provided herein is understood to include thereplacement of the generic substituent with specie substituents that areincluded within the particular genus, e.g., aryl may be independentlyreplaced with phenyl or naphthalenyl (also referred to as naphthyl) andthe like, such that the resulting compound is intended to be includedwithin the scope of the compounds described herein.

As used herein, the term “each instance of” when used in a phrase suchas “ . . . aryl, aryl-C₁₋₈alkyl, heterocyclyl andheterocyclyl-C₁₋₈alkyl, wherein each instance of aryl and heterocyclylis optionally substituted with one or two substituents . . . ” isintended to include optional, independent substitution on each of thearyl and heterocyclyl rings and on the aryl and heterocyclyl portions ofaryl-C₁₋₈alkyl and heterocyclyl-C₁₋₈alkyl.

As used herein, the term “optionally substituted” means that thespecified substituent variables, groups, radicals or moieties representthe scope of the genus and may be independently chosen as needed toreplace one or more hydrogen atoms on the designated atom of attachmentof a core molecule.

As used herein, the terms “stable compound” or “stable structure” mean acompound that is sufficiently robust to be isolated to a useful degreeof purity from a reaction mixture and formulations thereof into anefficacious therapeutic agent.

Compound names provided herein were obtained using ACD Labs Index Namesoftware provided by ACD Labs and/or ChemDraw Ultra software provided byCambridgeSoft®. When the compound name disclosed herein conflicts withthe structure depicted, the structure shown will supercede the use ofthe name to define the compound intended. Nomenclature for substituentradicals defined herein may differ slightly from the chemical name fromwhich they are derived; one skilled in the art will recognize that thedefinition of the substituent radical is intended to include the radicalas found in the chemical name.

The term “SMN,” unless otherwise specified herein, refers to the humanSMN1 gene, DNA or RNA, and/or human SMN2 gene, DNA or RNA. In a specificembodiment, the term “SMN1” refers to the human SMN1 gene, DNA or RNA.In another specific embodiment, the term “SMN2” refers to the human SMN2gene, DNA or RNA.

Nucleic acid sequences for the human SMN1 and SMN2 genes are known inthe art. For nucleic acid sequences of human SMN1, see, e.g., GenBankAccession Nos. DQ894095, NM_000344, NM_022874, and BC062723. For nucleicacid sequences of human SMN2, see, e.g., NM_022875, NM_022876,NM_022877, NM_017411, DQ894734 (Life Technologies, Inc. (formerlyInvitrogen), Carlsbad, Calif.), BC000908, BC070242, CR595484, CR598529,CR609539, U21914, and BC015308.

The SMN1 gene can be found on the forward strand of human chromosome 5from approximately nucleotide 70,220,768 to approximately nucleotide70,249,769. The approximate locations of exons 6, 7 and 8 and introns 6and 7 of SMN1 on human chromosome 5 are as follows:

70,241,893 to 70,242,003 exon 6;

70,242,004 to 70,247,767 intron 6;

70,247,768 to 70,247,821 exon 7;

70,247,822 to 70,248,265 intron 7; and,

70,248,266 to 70,248,839 exon 8.

The SMN2 gene can be found on the forward strand of human chromosome 5from approximately nucleotide 69,345,350 to approximately nucleotide69,374,349.

The approximate locations of exons 6, 7 and 8 and introns 6 and 7 ofSMN2 on human chromosome 5 are as follows:

69,366,468 to 69/366,578 exon 6;

69,366,579 to 69/372,347 intron 6;

69,372,348 to 69/372,401 exon 7;

69,372,402 to 69/372,845 intron 7; and,

69,372,846 to 69/373,419 exon 8.

In specific embodiments, the nucleotide sequences delineated above forexons 6, 7 and 8 and introns 6 and 7 of SMN1 are used in the SMN1minigene nucleic acid constructs described herein. In other specificembodiments, the nucleotide sequences of exons 6, 7 and 8 and introns 6and 7 of SMN2 in the examples provided herein are used in the SMN2minigene nucleic acid constructs described herein.

The term “Smn” or “Smn protein,” unless otherwise specified herein,refers to a human Smn protein that contains the amino acid residuesencoded by exons 1 through 7 of the SMN1 gene and/or SMN2 gene. In aspecific embodiment, the Smn protein is stable and functional in vitroand/or in vivo as assessed by methods known to one of skill in the art.In another specific embodiment, the Smn protein is the full-lengthprotein encoded by the human SMN1 gene and/or SMN2 gene. In anotherspecific embodiment, the Smn protein has the amino acid sequence foundat GenBank Accession No. NP_000335, AAC50473.1, AAA66242.1, or NP059107.

As used herein, the term “enhances the inclusion of exon 7 of SMN2 intomRNA that is transcribed from the SMN2 gene,” and analogous terms,unless otherwise specified herein, refers to the inclusion of thecomplete, intact, non-truncated sequence of exon 7 of SMN2 into themature mRNA that is transcribed from the SMN2 gene (i.e., resulting inthe production of full-length SMN2 mRNA) in vitro and/or in vivo, asassessed by methods known to one of skill in the art, such thatincreased levels of Smn protein are produced from the SMN2 gene in vitroand/or in vivo, as assessed by methods known to one of skill in the art;or, that increased expression of stable and functional Smn protein isproduced from the SMN2 gene in vitro and/or in vivo, as assessed bymethods known to one of skill in the art; or, that expression of thefusion protein encoded by the minigene is increased in vitro and/or invivo, as assessed by methods known to one of skill in the art; or, thatexpression of Smn protein produced from the SMN2 gene in a subject(e.g., an animal model for SMA or a human subject or an SMA patient) inneed thereof is increased.

As used herein, the term “enhances the inclusion of exon 7 of SMN1 intomRNA that is transcribed from the SMN1 gene,” and analogous terms,unless otherwise specified herein, refers to the inclusion of thecomplete, intact, non-truncated sequence of exon 7 of SMN1 into themature mRNA that is transcribed from the SMN1 gene (i.e., resulting inthe production of full-length SMN1 mRNA) in vitro and/or in vivo, asassessed by methods known to one of skill in the art, such thatincreased levels of Smn protein are produced from the SMN1 gene in vitroand/or in vivo, as assessed by methods known to one of skill in the art;or, that increased expression of stable and functional Smn protein isproduced from the SMN1 gene in vitro and/or in vivo, as assessed bymethods known to one of skill in the art; or, that expression of thefusion protein encoded by the minigene is increased in vitro and/or invivo, as assessed by methods known to one of skill in the art; or, thatexpression of Smn protein produced from the SMN1 gene in a subject(e.g., an animal model for SMA or a human subject) in need thereof isincreased.

As used herein, the term “substantial change” in the context of theamount of mRNA means that the amount of mRNA does not change by astatistically significant amount, e.g., a p value less than a valueselected from 0.1, 0.05, 0.01, 0.005, 0.001, 0.0005, 0.0001, 0.00005 or0.00001.

As used herein, the terms “subject” and “patient” are usedinterchangeably to refer to an animal or any living organism havingsensation and the power of voluntary movement, and which requires forits existence oxygen and organic food. Nonlimiting examples includemembers of the human, equine, porcine, bovine, rattus, murine, canineand feline species. In some embodiments, the subject is a mammal or awarm-blooded vertebrate animal. In certain embodiments, the subject is anon-human animal. In specific embodiments, the subject is a human. Inone specific embodiment, the subject is a human SMA patient.

As used herein, the term “elderly human” refers to a human 65 years oldor older.

As used herein, the term “human adult” refers to a human that is 18years or older.

As used herein, the term “human child” refers to a human that is 1 yearto 18 years old.

As used herein, the term “human infant” refers to a newborn to 1 yearold year human.

As used herein, the term “human toddler” refers to a human that is 1year to 3 years old.

Compound Forms

As used herein, the terms “a compound of Formula (Ia),” “a compound ofFormula (Ia1),” “a compound of Formula (Ia2),” “a compound of Formula(Ia3),” “a compound of Formula (Ia4),” “a compound of Formula (II),” “acompound of Formula (IIa),” “a compound of Formula (IIa1),” “a compoundof Formula (IIa2),” “a compound of Formula (IIa3),” “a compound ofFormula (IIa4),” “a compound of Formula (III),” “a compound of Formula(IIIa),” “a compound of Formula (IIIa1),” “a compound of Formula(IIIa2),” “a compound of Formula (IIIa3),” “a compound of Formula(IIIa4),” “a compound of Formula (IV),” “a compound of Formula (IVa),”“a compound of Formula (IVa1),” “a compound of Formula (IVa2),” “acompound of Formula (V),” “a compound of Formula (Va),” “a compound ofFormula (Va1),” “a compound of Formula (Va2),” “a compound of Formula(VI),” “a compound of Formula (VIa),” “a compound of Formula (VIa1),” “acompound of Formula (VIa2),” “a compound of Formula (VIa3),” “a compoundof Formula (VIa4),” “a compound of Formula (VII),” “a compound ofFormula (VIIa),” “a compound of Formula (VIIa1),” “a compound of Formula(VIIa2),” “a compound of Formula (VIII),” “a compound of Formula(VIIIa),” “a compound of Formula (VIIIa1),” “a compound of Formula(VIIIa2),” “a compound of Formula (IX),” “a compound of Formula (IXa),”“a compound of Formula (IXa1),” “a compound of Formula (IXa2),” “acompound of Formula (IXa3),” “a compound of Formula (IXa4),” “a compoundof Formula (X),” “a compound of Formula (Xa),” “a compound of Formula(Xa1),” “a compound of Formula (Xa2),” “a compound of Formula (XI),” “acompound of Formula (XIa),” “a compound of Formula (XIa1),” “a compoundof Formula (XIa2),” “a compound of Formula (XII),” “a compound ofFormula (XIIa),” “a compound of Formula (XIIa1),” “a compound of Formula(XIIa2),” “a compound of Formula (XIIa3),” “a compound of Formula(XIIa4),” “a compound of Formula (XIII),” “a compound of Formula(XIIIa),” “a compound of Formula (XIIIa1),” “a compound of Formula(XIIIa2),” “a compound of Formula (XIV),” “a compound of Formula(XIVa),” “a compound of Formula (XIVa1),” and “a compound of Formula(XIVa2),” each refer to subgenera of the compound of Formula (I) or aform thereof.

Rather than repeat embodiments for the various subgenera of the compoundof Formula (I), in certain embodiments, the term “a compound of Formula(I) or a form thereof” is used to inclusively to refer to a compound ofFormula (Ia) or a form thereof, a compound of Formula (Ia1) or a formthereof, a compound of Formula (Ia2) or a form thereof, a compound ofFormula (Ia3) or a form thereof, a compound of Formula (Ia4) or a formthereof, a compound of Formula (II) or a form thereof, a compound ofFormula (IIa) or a form thereof, a compound of Formula (IIa1) or a formthereof, a compound of Formula (IIa2) or a form thereof, a compound ofFormula (IIa3) or a form thereof, a compound of Formula (IIa4) or a formthereof, a compound of Formula (III) or a form thereof, a compound ofFormula (IIIa) or a form thereof, a compound of Formula (IIIa1) or aform thereof, a compound of Formula (IIIa2) or a form thereof, acompound of Formula (IIIa3) or a form thereof, a compound of Formula(IIIa4) or a form thereof, a compound of Formula (IV) or a form thereof,a compound of Formula (IVa) or a form thereof, a compound of Formula(IVa1) or a form thereof, a compound of Formula (IVa2) or a formthereof, a compound of Formula (V) or a form thereof, a compound ofFormula (Va) or a form thereof, a compound of Formula (Va1) or a formthereof, a compound of Formula (Va2) or a form thereof, a compound ofFormula (VI) or a form thereof, a compound of Formula (VIa) or a formthereof, a compound of Formula (VIa1) or a form thereof, a compound ofFormula (VIa2) or a form thereof, a compound of Formula (VIa3) or a formthereof, a compound of Formula (VIa4) or a form thereof, a compound ofFormula (VII) or a form thereof, a compound of Formula (VIIa) or a formthereof, a compound of Formula (VIIa1) or a form thereof, a compound ofFormula (VIIa2) or a form thereof, a compound of Formula (VIII) or aform thereof, a compound of Formula (VIIIa) or a form thereof, acompound of Formula (VIIIa1) or a form thereof, a compound of Formula(VIIIa2) or a form thereof, a compound of Formula (IX) or a formthereof, a compound of Formula (IXa) or a form thereof, a compound ofFormula (IXa1) or a form thereof, a compound of Formula (IXa2) or a formthereof, a compound of Formula (IXa3) or a form thereof, a compound ofFormula (IXa4) or a form thereof, a compound of Formula (X) or a formthereof, a compound of Formula (Xa) or a form thereof, a compound ofFormula (Xa1) or a form thereof, a compound of Formula (Xa2) or a formthereof, a compound of Formula (XI) or a form thereof, a compound ofFormula (XIa) or a form thereof, a compound of Formula (XIa1) or a formthereof, a compound of Formula (XIa2) or a form thereof, a compound ofFormula (XII) or a form thereof, a compound of Formula (XIIa) or a formthereof, a compound of Formula (XIIa1) or a form thereof, a compound ofFormula (XIIa2) or a form thereof, a compound of Formula (XIIa3) or aform thereof, a compound of Formula (XIIa4) or a form thereof, acompound of Formula (XIII) or a form thereof, a compound of Formula(XIIIa) or a form thereof, a compound of Formula (XIIIa1) or a formthereof, a compound of Formula (XIIIa2) or a form thereof, a compound ofFormula (XIV) or a form thereof, a compound of Formula (XIVa) or a formthereof, a compound of Formula (XIVa1) or a form thereof or a compoundof Formula (XIVa2) or a form thereof, either separately or together.

Thus, embodiments and references to “a compound of Formula (I)” areintended to be inclusive of compounds of Formula (Ia), Formula (Ia1),Formula (Ia2), Formula (Ia3), Formula (Ia4), Formula (II), Formula(IIa), Formula (IIa1), Formula (IIa2), Formula (IIa3), Formula (IIa4),Formula (III), Formula (IIIa), Formula (IIIa1), Formula (IIIa2), Formula(IIIa3), Formula (IIIa4), Formula (IV), Formula (IVa), Formula (IVa1),Formula (IVa2), Formula (V), Formula (Va), Formula (Va1), Formula (Va2),Formula (VI), Formula (VIa), Formula (VIa1), Formula (VIa2), Formula(VIa3), Formula (VIa4), Formula (VII), Formula (VIIa), Formula (VIIa1),Formula (VIIa2), Formula (VIII), Formula (VIIIa), Formula (VIIIa1),Formula (VIIIa2), Formula (IX), Formula (IXa), Formula (IXa1), Formula(IXa2), Formula (IXa3), Formula (IXa4), Formula (X), Formula (Xa),Formula (Xa1), Formula (Xa2), Formula (XI), Formula (XIa), Formula(XIa1), Formula (XIa2), Formula (XII), Formula (XIIa), Formula (XIIa1),Formula (XIIa2), Formula (XIIa3), Formula (XIIa4), Formula (XIII),Formula (XIIIa), Formula (XIIIa1), Formula (XIIIa2), Formula (XIV),Formula (XIVa), Formula (XIVa1) and Formula (XIVa2).

As used herein, the term “form” means a compound of Formula (I) selectedfrom a free acid, free base, salt, isotopologue, stereoisomer, racemate,enantiomer, diastereomer, or tautomer thereof.

In certain embodiments described herein, the form of the compound ofFormula (I) is a selected from a salt, isotopologue, stereoisomer,racemate, enantiomer, diastereomer or tautomer thereof.

In certain embodiments described herein, the form of the compound ofFormula (I) is a selected from a free acid, isotopologue, stereoisomer,racemate, enantiomer, diastereomer or tautomer thereof.

In certain embodiments described herein, the form of the compound ofFormula (I) is a selected from a free base, isotopologue, stereoisomer,racemate, enantiomer, diastereomer or tautomer thereof.

In certain embodiments described herein, the form of the compound ofFormula (I) is a free acid, free base or salt thereof.

In certain embodiments described herein, the form of the compound ofFormula (I) is an isotopologue thereof.

In certain embodiments described herein, the form of the compound ofFormula (I) is a stereoisomer, racemate, enantiomer or diastereomerthereof.

In certain embodiments described herein, the form of the compound ofFormula (I) is a tautomer thereof.

In certain embodiments described herein, the form of the compound ofFormula (I) is a pharmaceutically acceptable form.

In certain embodiments described herein, the compound of Formula (I) ora form thereof is isolated for use.

As used herein, the term “isolated” means the physical state of acompound of Formula (I) or a form thereof after being isolated and/orpurified from a synthetic process (e.g., from a reaction mixture) ornatural source or combination thereof according to an isolation orpurification process or processes described herein or which are wellknown to the skilled artisan (e.g., chromatography, recrystallizationand the like) in sufficient purity to be characterizable by standardanalytical techniques described herein or well known to the skilledartisan.

As used herein, the term “protected” means that a functional group on acompound of Formula (I) is in a form modified to preclude undesired sidereactions at the protected site when the compound is subjected to areaction. Suitable protecting groups will be recognized by those withordinary skill in the art as well as by reference to standard textbookssuch as, for example, T. W. Greene et al, Protective Groups in OrganicSynthesis (1991), Wiley, New York.

Prodrugs of a compound of Formula (I) or a form thereof are alsocontemplated herein.

As used herein, the term “prodrug” means that a functional group on acompound of Formula (I) is in a form (e.g., acting as an active orinactive drug precursor) that is transformed in vivo to yield an activeor more active compound of Formula (I) or a form thereof. Thetransformation may occur by various mechanisms (e.g., by metabolicand/or non-metabolic chemical processes), such as, for example, byhydrolysis and/or metabolism in blood, liver and/or other organs andtissues. A discussion of the use of prodrugs is provided by V. J.Stella, et. al., “Biotechnology: Pharmaceutical Aspects, Prodrugs:Challenges and Rewards,” American Association of PharmaceuticalScientists and Springer Press, 2007.

In one example, when a compound of Formula (I) or a form thereofcontains a carboxylic acid functional group, a prodrug can comprise anester formed by the replacement of the hydrogen atom of the acid groupwith a functional group such as alkyl and the like. In another example,when a compound of Formula (I) or a form thereof contains an alcoholfunctional group, a prodrug can be formed by the replacement of thehydrogen atom of the alcohol group with a functional group such as alkylor substituted carbonyl and the like. In another example, when acompound of Formula (I) or a form thereof contains an amine functionalgroup, a prodrug can be formed by the replacement of one or more aminehydrogen atoms with a functional group such as alkyl or substitutedcarbonyl. In another example, when a compound of Formula (I) or a formthereof contains a hydrogen substituent, a prodrug can be formed by thereplacement of one or more hydrogen atoms with an alkyl substituent.

Pharmaceutically acceptable prodrugs of compounds of Formula (I) or aform thereof include those compounds substituted with one or more of thefollowing groups: carboxylic acid esters, sulfonate esters, amino acidesters phosphonate esters, mono-, di- or triphosphate esters or alkylsubstituents where appropriate. As described herein, it is understood bya person of ordinary skill in the art that one or more of suchsubstituents may be used to provide a compound of Formula (I) or a formthereof for use as a prodrug.

The compounds of Formula (I) can form salts which are intended to beincluded within the scope of this description. Reference to a compoundof Formula (I) herein is understood to include reference to saltsthereof, unless otherwise indicated. The term “salt(s)”, as employedherein, denotes acidic salts formed with inorganic and/or organic acids,as well as basic salts formed with inorganic and/or organic bases. Inaddition, when a compound of Formula (I) contains both a basic moiety,such as, but not limited to a pyridine or imidazole, and an acidicmoiety, such as, but not limited to a carboxylic acid, zwitterions(“inner salts”) may be formed and are included within the term “salt(s)”as used herein.

The term “pharmaceutically acceptable salt(s)”, as used herein, meansthose salts of compounds described herein that are safe and effective(i.e., non-toxic, physiologically acceptable) for use in mammals andthat possess biological activity, although other salts are also useful.Salts of the compounds of Formula (I) may be formed, for example, byreacting a compound of Formula (I) with an amount of acid or base, suchas an equivalent or stoichiometric amount, in a medium such as one inwhich the salt precipitates or in an aqueous medium followed bylyophilization.

Pharmaceutically acceptable salts include one or more salts of acidic orbasic groups present in compounds described herein. Embodiments of acidaddition salts include, but are not limited to, an acetate, diacetate,acid phosphate, ascorbate, benzoate, benzenesulfonate, bisulfate,bitartrate, borate, butyrate, chloride, citrate, camphorate,camphorsulfonate, ethanesulfonate, formate, fumarate, gentisinate,gluconate, glucaronate, glutamate, hydrobromide, hydrochloride,dihydrochloride, trihydrochloride, hydroiodide, isonicotinate, lactate,maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate,pamoate, pantothenate, phosphate, propionate, saccharate, salicylate,succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also knownas tosylate), trifluoroacetate, trifluoroacetic acid salt and the like.One or more embodiments of acid addition salts include chloride,hydrobromide, hydrochloride, dihydrochloride, trihydrochloride, acetate,diacetate, trifluoroacetate, trifluoroacetic acid salt and the like.More particular embodiments include a chloride, hydrobromide,hydrochloride, dihydrochloride, trifluoroacetate, trifluoroacetic acidsalt and the like.

Additionally, acids which are generally considered suitable for theformation of pharmaceutically useful salts from basic pharmaceuticalcompounds are discussed, for example, by P. Stahl et al, Camille G.(eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use.(2002) Zurich: Wiley-VCH; S. Berge et al, Journal of PharmaceuticalSciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics(1986) 33, 201-217; Anderson et al, The Practice of Medicinal Chemistry(1996), Academic Press, New York; and in The Orange Book (see, websitefor Food & Drug Administration, Washington, D.C.). These disclosures areincorporated herein by reference thereto.

Suitable basic salts include, but are not limited to, aluminum,ammonium, calcium, lithium, magnesium, potassium, sodium, zinc, anddiethanolamine salts. Certain compounds described herein can also formpharmaceutically acceptable salts with organic bases (for example,organic amines) such as, but not limited to, dicyclohexylamines,tert-butyl amines and the like, and with various amino acids such as,but not limited to, arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides andiodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g., decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g., benzyl andphenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the description herein and all suchacid and base salts are considered equivalent to the free forms of thecorresponding compounds for the purposes described herein.

Compounds of Formula I and forms thereof may further exist in atautomeric form. All such tautomeric forms are contemplated herein aspart of the present description.

The compounds of Formula (I) may contain asymmetric or chiral centers,and, therefore, may exist in different stereoisomeric forms. The presentdescription is intended to include all stereoisomeric forms of thecompounds of Formula (I) as well as mixtures thereof, including racemicmixtures.

The compounds of Formula (I) described herein may include one or morechiral centers, and as such may exist as racemic mixtures (R S) or assubstantially pure enantiomers and diastereomers. The compounds may alsoexist as substantially pure (R) or (S) enantiomers (when one chiralcenter is present). In one embodiment, the compounds of Formula (I)described herein are (S) isomers and may exist as enantiomerically purecompositions substantially comprising only the (S) isomer. In anotherembodiment, the compounds of Formula (I) described herein are (R)isomers and may exist as enantiomerically pure compositionssubstantially comprising only the (R) isomer. As one of skill in the artwill recognize, when more than one chiral center is present, thecompounds of Formula (I) described herein may also include portionsdescribed as an (R,R), (R,S), (S,R) or (S,S) isomer, as defined by IUPACNomenclature Recommendations.

As used herein, the term “substantially pure” refers to compoundsconsisting substantially of a single isomer in an amount greater than orequal to 90%, in an amount greater than or equal to 92%, in an amountgreater than or equal to 95%, in an amount greater than or equal to 98%,in an amount greater than or equal to 99%, or in an amount equal to 100%of the single isomer.

In one aspect, a compound of Formula (I) is a substantially pure (S)enantiomer present in an amount greater than or equal to 90%, in anamount greater than or equal to 92%, in an amount greater than or equalto 95%, in an amount greater than or equal to 98%, in an amount greaterthan or equal to 99%, or in an amount equal to 100%.

In one aspect, a compound of Formula (I) is a substantially pure (R)enantiomer present in an amount greater than or equal to 90%, in anamount greater than or equal to 92%, in an amount greater than or equalto 95%, in an amount greater than or equal to 98%, in an amount greaterthan or equal to 99%, or in an amount equal to 100%.

As used herein, a “racemate” is any mixture of isometric forms that arenot “enantiomerically pure”, including mixtures such as, withoutlimitation, in a ratio of about 50/50, about 60/40, about 70/30, about80/20, about 85/15 or about 90/10.

In addition, the present description embraces all geometric andpositional isomers. For example, if a compound of Formula (I)incorporates a double bond or a fused ring, both the cis- andtrans-forms, as well as mixtures, are embraced within the scope of thedescription herein.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by use of chiral HPLC column or other chromatographic methodsknown to those skilled in the art.

Enantiomers can also be separated by converting the enantiomeric mixtureinto a diastereomeric mixture by reaction with an appropriate opticallyactive compound (e.g., chiral auxiliary such as a chiral alcohol orMosher's acid chloride), separating the diastereomers and converting(e.g., hydrolyzing) the individual diastereomers to the correspondingpure enantiomers. Also, some of the compounds of Formula (I) may beatropisomers (e.g., substituted biaryls) and are considered part of thisdescription.

All stereoisomer forms (for example, geometric isomers, optical isomers,positional isomers and the like) of the present compounds (includingsalts, solvates, esters and prodrugs and transformed prodrugs thereof)which may exist due to asymmetric carbons on various substituents,including enantiomeric forms (which may exist even in the absence ofasymmetric carbons), rotameric forms, atropisomers, diastereomeric formsand regioisomeric forms are contemplated within the scope of thedescription herein. For example, if a compound of Formula (I)incorporates a double bond or a fused ring, both the cis- andtrans-forms, as well as mixtures thereof, are embraced within the scopeof the description herein. Also, for example, all keto-enol andimine-enamine tautomeric forms of the compounds are included in thedescription herein. Individual stereoisomers of the compounds of Formula(I) described herein may, for example, be substantially free of otherisomers, or may be present in a racemic mixture, as described supra.

The use of the terms “salt,” “prodrug” and “transformed prodrug” areintended to equally apply to the salts, prodrugs and transformedprodrugs of all contemplated isotopologues, stereoisomers, racemates ortautomers of the instant compounds.

The term “isotopologue” refers to isotopically-enriched compounds whichare identical to those recited herein, but for the fact that one or moreatoms are replaced by an atom having an atomic mass or mass numberdifferent from the atomic mass or mass number usually found in nature.Examples of isotopes that can be incorporated into compounds describedherein include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorus, fluorine and chlorine, such as H², H³, C¹³, C¹⁴, N¹⁵, O¹⁸,O¹⁷, P³¹, P³², S³⁵, F¹⁸, Cl³⁵ and Cl³⁶, respectively, each of which isalso within the scope of this description.

Certain isotopically-enriched compounds described herein (e.g., thoselabeled with H³ and C¹⁴) are useful in compound and/or substrate tissuedistribution assays. Tritiated (i.e., H³) and carbon-14 (i.e., C¹⁴)isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium (i.e., “deuterium enriched”) may afford certain therapeuticadvantages resulting from greater metabolic stability (e.g., increasedin vivo half-life or reduced dosage requirements) and hence may bepreferred in some circumstances. Isotopically-enriched compounds ofFormula (I) can generally be prepared using procedures known to personsof ordinary skill in the art by substituting an appropriateisotopically-enriched reagent for a non-isotopically-enriched reagent.

When the compounds are enriched with deuterium, thedeuterium-to-hydrogen ratio on the deuterated atoms of the moleculesubstantially exceeds the naturally occurring deuterium-to-hydrogenratio.

An embodiment described herein may include an isotopologue form of thecompound of Formula (I), wherein the isotopologue is substituted on oneor more atom members of the compound of Formula (I) with one or moredeuterium atoms in place of one or more hydrogen atoms.

An embodiment described herein may include a compound of Formula (I) andforms thereof, wherein a carbon atom may have from 1 to 3 hydrogen atomsoptionally replaced with deuterium.

One or more compounds described herein may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and the description herein is intended toembrace both solvated and unsolvated forms.

As used herein, the term “solvate” means a physical association of acompound described herein with one or more solvent molecules. Thisphysical association involves varying degrees of ionic and covalentbonding, including hydrogen bonding. In certain instances the solvatewill be capable of isolation, for example when one or more solventmolecules are incorporated in the crystal lattice of the crystallinesolid. As used herein, “solvate” encompasses both solution-phase andisolatable solvates. Non-limiting examples of suitable solvates includeethanolates, methanolates, and the like.

One or more compounds described herein may optionally be converted to asolvate. Preparation of solvates is generally known. A typical,non-limiting process involves dissolving a compound in a desired amountof the desired solvent (organic or water or mixtures thereof) at ahigher than ambient temperature, and cooling the solution at a ratesufficient to form crystals which are then isolated by standard methods.Analytical techniques such as, for example infrared spectroscopy, showthe presence of the solvent (or water) in the crystals as a solvate (orhydrate).

As used herein, the term “hydrate” means a solvate wherein the solventmolecule is water.

Polymorphic crystalline and amorphous forms of the compounds of Formula(I), and of the salts, solvates, esters and prodrugs of the compounds ofFormula (I), are further intended to be included in the scope of thecompounds described herein.

Compound Uses

Compounds of Formula (I) or a form thereof that enhance inclusion ofexon 7 of SMN2 into mRNA that is transcribed from the SMN2 gene aredescribed herein. Such compounds of Formula (I) or a form thereof havebeen shown to enhance the inclusion of exon 7 of SMN2 into mRNA that istranscribed from the SMN2 gene using the assays described herein (seeBiological example section, infra). Accordingly, compounds of Formula(I) or a form thereof have utility as enhancers for the inclusion ofexon 7 of SMN2 into mRNA that is transcribed from the SMN2 gene.

Compounds of Formula (I) or a form thereof for enhancing inclusion ofexon 7 of SMN1 into mRNA that is transcribed from the SMN1 gene aredescribed herein. Such compounds of Formula (I) or a form thereof mayenhance inclusion of exon 7 of SMN1 into mRNA that is transcribed fromthe SMN1 gene using, e.g., an SMN1 minigene assay. Accordingly,compounds of Formula (I) or a form thereof may have utility as enhancersfor the inclusion of exon 7 of SMN1 into mRNA that is transcribed fromthe SMN1 gene.

In one aspect, provided herein are methods for modulating the inclusionof exon 7 of SMN2 into RNA transcribed from the SMN2 gene, comprisingcontacting a human cell with a compound of Formula (I) or a formthereof. In a specific embodiment, provided herein are methods formodulating the inclusion of exon 7 of SMN2 into RNA transcribed from theSMN2 gene, comprising contacting a human cell with a compound of Formula(I) or a form thereof that modulates the expression of an SMN2 minigenedescribed herein or in International Publication No. WO2009/151546 orU.S. Patent Application Publication No. 2011/0086833, each of which isincorporated herein by reference in its entirety. In one embodiment, theminigene is a minigene described in the Examples of InternationalPublication No. WO2009/151546 or U.S. Patent Application Publication No.2011/0086833. In another embodiment, the minigene is the minigenedescribed in Biological Example 1, infra. The human cell can becontacted with a compound of Formula (I) or a form thereof in vitroand/or in vivo, e.g., in a non-human animal or in a human. In a specificembodiment, the human cell is from or in a human. In another specificembodiment, the human cell is from or in a human SMA patient. In anotherspecific embodiment, the human cell is from or in a human SMA patient,wherein SMA is caused by an inactivating mutation or deletion in theSMN1 gene on both chromosomes, resulting in a loss of SMN1 genefunction. In another embodiment, the human cell is a human cell from ahuman SMA patient. In certain embodiments, the human cell is from a cellline, such as GM03813, GM00232, GM09677, and/or GM23240 (available fromCoriell Institute). In one embodiment, the compound is a compound ofFormula (I) or a form thereof.

In a specific embodiment, provided herein is a method for enhancing theinclusion of exon 7 of SMN2 into mRNA that is transcribed from the SMN2gene, comprising contacting a human cell with a compound of Formula (I)or a form thereof. In another embodiment, provided herein is a methodfor enhancing the inclusion of exon 7 of SMN2 into mRNA that istranscribed from the SMN2 gene, comprising contacting a human cell witha compound of Formula (I) or a form thereof that enhances the expressionof an SMN2 minigene described herein or in International Publication No.WO2009/151546 or U.S. Patent Application Publication No. 2011/0086833,each of which is incorporated herein by reference in its entirety. Inone embodiment, the minigene is a minigene described in the Examples ofInternational Publication No. WO2009/151546 or U.S. Patent ApplicationPublication No. 2011/0086833. In another embodiment, the minigene is theminigene described in Biological Example 1, infra. The human cell can becontacted with a compound of Formula (I) or a form thereof in vitroand/or in vivo, e.g., in a non-human animal or in a human. In a specificembodiment, the human cell is from or in a human. In another specificembodiment, the human cell is from or in a human SMA patient. In anotherspecific embodiment, the human cell is from or in a human SMA patient,wherein SMA is caused by an inactivating mutation or deletion in theSMN1 gene on both chromosomes, resulting in a loss of SMN1 genefunction. In another embodiment, the human cell is a human cell from ahuman SMA patient. In certain embodiments, the human cell is from a cellline, such as GM03813, GM00232, GM09677, and/or GM23240 (available fromCoriell Institute). In one embodiment, the compound is a compound ofFormula (I) or a form thereof.

In another aspect, provided herein are methods for enhancing theinclusion of exon 7 of SMN1 into RNA transcribed from the SMN1 gene,comprising contacting a human cell with a compound of Formula (I) or aform thereof. In a specific embodiment, provided herein are methods forenhancing the inclusion of exon 7 of SMN1 into RNA transcribed from theSMN1 gene, comprising contacting a human cell with a compound of Formula(I) or a form thereof. In another specific embodiment, provided hereinare methods for enhancing the inclusion of exon 7 of SMN1 into RNAtranscribed from the SMN1 gene, comprising contacting a human cell witha compound of Formula (I) or a form thereof that modulates theexpression of an SMN1 minigene described in International PublicationNo. WO2009/151546 or U.S. Patent Application Publication No.2011/0086833, each of which is incorporated herein by reference in itsentirety. In one embodiment, the minigene is a minigene described in theExamples of International Publication No. WO2009/151546 or U.S. PatentApplication Publication No. 2011/0086833. The human cell can becontacted with a compound of Formula (I) or a form thereof in vitroand/or in vivo, e.g., in a non-human animal or in a human. In a specificembodiment, the human cell is from or in a human. In another specificembodiment, the human cell is from or in a human SMA patient. In oneembodiment, the compound is a compound of Formula (I) or a form thereof.

In specific embodiments, provided herein are methods for enhancing theinclusion of exon 7 of SMN1 and SMN2 into RNA transcribed from the SMN1and SMN2 genes, comprising contacting a human cell with a compound ofFormula (I) or a form thereof. The human cell can be contacted with acompound of Formula (I) or a form thereof in vitro and/or in vivo, e.g.,in a non-human animal or in a human. In a specific embodiment, the humancell is from or in a human. In another specific embodiment, the humancell is from or in a human SMA patient. In one embodiment, the compoundis a compound of Formula (I) or a form thereof.

In another aspect, provided herein is a method for modulating theinclusion of exon 7 of SMN2 into RNA transcribed from the SMN2 gene,comprising administering to a non-human animal model for SMA a compoundof Formula (I) or a form thereof. In a specific embodiment, providedherein is a method for modulating the inclusion of exon 7 of SMN2 intoRNA transcribed from the SMN2 gene, comprising administering to anon-human animal model for SMA a compound of Formula (I) or a formthereof that modulates the expression of an SMN2 minigene describedherein or in International Publication No. WO2009/151546 or U.S. PatentApplication Publication No. 2011/0086833, each of which is incorporatedherein by reference in its entirety. In one embodiment, the minigene isa minigene described in the Examples of International Publication No.WO2009/151546 or U.S. Patent Application Publication No. 2011/0086833.In another embodiment, the minigene is the minigene described inBiological Example 1, infra. In a specific embodiment, the compound is acompound of Formula (I) or a form thereof.

In a specific embodiment, provided herein is a method for enhancing theinclusion of exon 7 of SMN2 into mRNA that is transcribed from the SMN2gene, comprising administering to a non-human animal model for SMA acompound of Formula (I) or a form thereof. In another specificembodiment, provided herein is a method for enhancing the inclusion ofexon 7 of SMN2 into mRNA that is transcribed from the SMN2 gene,comprising administering to a non-human animal model for SMA a compoundof Formula (I) or a form thereof that enhances the expression of an SMN2minigene described herein or in International Publication No.WO2009/151546 or U.S. Patent Application Publication No. 2011/0086833,each of which is incorporated herein by reference in its entirety. Inone embodiment, the minigene is a minigene described in the Examples ofInternational Publication No. WO2009/151546 or U.S. Patent ApplicationPublication No. 2011/0086833. In another embodiment, the minigene is theminigene described in Biological Example 1, infra. In a specificembodiment, the compound is a compound of Formula (I) or a form thereof.

In another aspect, provided herein is a method for enhancing theinclusion of exon 7 of SMN1 into RNA transcribed from the SMN1 gene,comprising administering to a non-human animal model for SMA a compoundof Formula (I) or a form thereof. In a specific embodiment, providedherein is a method for enhancing the inclusion of exon 7 of SMN1 intoRNA transcribed from the SMN1 gene, comprising administering to anon-human animal model for SMA a compound of Formula (I) or a formthereof that modulates the expression of an SMN1 minigene describedherein or in International Publication No. WO2009/151546 or U.S. PatentApplication Publication No. 2011/0086833, each of which is incorporatedherein by reference in its entirety. In one embodiment, the minigene isa minigene described in the Examples of International Publication No.WO2009/151546 or U.S. Patent Application Publication No. 2011/0086833.In a specific embodiment, the compound is a compound of Formula (I) or aform thereof.

In specific embodiments, provided herein is a method for enhancing theinclusion of exon 7 of SMN1 and SMN2 into RNA transcribed from the SMN1and SMN2 genes, comprising administering to a non-human animal model forSMA a compound of Formula (I) or a form thereof. In a specificembodiment, the compound is a compound of Formula (I) or a form thereof.

In another aspect, provided herein is a method for increasing the amountof Smn protein, comprising contacting a human cell with a compound ofFormula (I) or a form thereof. In a specific embodiment, provided hereinis a method for increasing the amount of Smn protein, comprisingcontacting a human cell with a compound of Formula (I) that enhances theinclusion of exon 7 of SMN2 into mRNA that is transcribed from the SMN2gene. In another specific embodiment, provided herein is a method forincreasing the amount of Smn protein, comprising contacting a human cellwith a compound of Formula (I) that enhances the inclusion of exon 7 ofSMN1 and/or SMN2 into mRNA that is transcribed from the SMN1 and/or SMN2gene. The human cell can be contacted with a compound of Formula (I) ora form thereof in vitro and/or in vivo, e.g., in a non-human animal orin a human. In a specific embodiment, the human cell is from or in ahuman. In another specific embodiment, the human cell is from or in ahuman SMA patient. In another specific embodiment, the human cell isfrom or in a human SMA patient, wherein SMA is caused by an inactivatingmutation or deletion in the SMN1 gene on both chromosomes, resulting ina loss of SMN1 gene function. In another embodiment, the human cell is ahuman cell from a human SMA patient. In certain embodiments, the humancell is from a cell line, such as GM03813, GM00232, GM09677, and/orGM23240 (available from Coriell Institute). In one embodiment, thecompound is a compound of Formula (I) or a form thereof.

In another aspect, provided herein is a method for increasing the amountof Smn protein, comprising administering to a non-human animal model forSMA a compound of Formula (I) or a form thereof. In a specificembodiment, provided herein is a method for increasing the amount of Smnprotein, comprising administering to a non-human animal model for SMA acompound of Formula (I) that enhances the inclusion of exon 7 of SMN2into mRNA that is transcribed from the SMN2 gene in, e.g., a cell-basedor cell-free assay, such as described in the Biological Examples, infra.In another specific embodiment, provided herein is a method forincreasing the amount of Smn protein, comprising administering to anon-human animal model for SMA a compound of Formula (I) that enhancesthe inclusion of exon 7 of SMN1 and/or SMN2 into mRNA that istranscribed from the SMN1 and/or SMN2 gene in, e.g., a cell-based orcell-free assay.

In one embodiment, the compound of Formula (I) enhances the expressionof a minigene described herein or in International Publication No.WO2009/151546 or U.S. Patent Application Publication No. 2011/0086833,each of which is incorporated herein by reference in its entirety. In aspecific embodiment, the compound of Formula (I) enhances the expressionof a minigene described in the Examples of International Publication No.WO2009/151546 or U.S. Patent Application Publication No. 2011/0086833.In another specific embodiment, the compound of Formula (I) enhances theexpression of a minigene described in Biological Example 1, infra. Inone embodiment, the compound is a compound of Formula (I) or a formthereof.

In one embodiment, provided herein is the use of a compound of Formula(I) or a form thereof for the preparation of a medicament that enhancesthe inclusion of exon 7 of SMN2 into mRNA that is transcribed from theSMN2 gene. In another embodiment, provided herein is the use of acompound of Formula (I) or a form thereof for the preparation of amedicament that enhances the inclusion of exon 7 of SMN2 into mRNA thatis transcribed from the SMN2 gene, thereby increasing expression of Smnprotein in a human subject in need thereof. In a particular embodiment,the compound of Formula (I) or a form thereof enhances the inclusion ofexon 7 of SMN2 into mRNA that is transcribed from the SMN2 gene in anassay described herein (see, e.g., the Biological Examples, infra). In aspecific embodiment, the compound is a compound of Formula (I) or a formthereof.

In one embodiment, provided herein is the use of a compound of Formula(I) or a form thereof for the preparation of a medicament that enhancesthe inclusion of exon 7 of SMN1 and/or SMN2 into mRNA that istranscribed from the SMN1 and/or SMN2 gene. In another embodiment,provided herein is the use of a compound of Formula (I) or a formthereof for the preparation of a medicament that enhances the inclusionof exon 7 of SMN1 and/or SMN2 into mRNA that is transcribed from theSMN1 and/or SMN2 gene, thereby increasing expression of Smn protein in ahuman subject in need thereof. In a specific embodiment, the compound isa compound of Formula (I) or a form thereof.

In another aspect, provided herein are methods for enhancing theinclusion of exon 7 of SMN2 into mRNA that is transcribed from the SMN2gene in a human subject in need thereof, comprising administering to thehuman subject an effective amount of a compound of Formula (I) or a formthereof. In a specific embodiment, provided herein is a method forenhancing the inclusion of exon 7 of SMN2 into mRNA that is transcribedfrom the SMN2 gene in a human subject in need thereof, comprisingadministering to the human subject an effective amount a compound ofFormula (I) or a form thereof that enhances the inclusion of exon 7 ofSMN2 into mRNA that is transcribed from the SMN2 gene as determined inan assay described herein (see, e.g., the Biological Examples, infra).In specific embodiments, the effective amount of the compound of Formula(I) or a form thereof is administered to the human subject in apharmaceutical composition comprising a pharmaceutically acceptablecarrier, excipient or diluent. In a particular embodiment, the compoundof Formula (I) or a form thereof enhances the inclusion of exon 7 ofSMN2 into mRNA that is transcribed from the SMN2 gene in an assaydescribed herein (see, e.g., the Biological Examples, infra). In aspecific embodiment, the human subject is a human SMA patient. Inanother specific embodiment, the human subject is a human SMA patient,wherein SMA is caused by an inactivating mutation or deletion in theSMN1 gene on both chromosomes, resulting in a loss of SMN1 genefunction. In one embodiment, the compound is a compound of Formula (I)or a form thereof.

In another aspect, provided herein are methods for enhancing theinclusion of exon 7 of SMN1 into mRNA that is transcribed from the SMN1gene in a human subject in need thereof, comprising administering to thehuman subject an effective amount of a compound of Formula (I) or a formthereof. In a particular embodiment, the compound of Formula (I) or aform thereof enhances the inclusion of exon 7 of SMN1 into mRNA that istranscribed from the SMN1 gene in an assay described in InternationalPublication No. WO2009/151546 or U.S. Patent Application Publication No.2011/0086833. In specific embodiments, the effective amount of thecompound of Formula (I) or a form thereof is administered to the humansubject in a pharmaceutical composition comprising a pharmaceuticallyacceptable carrier, excipient or diluent. In a specific embodiment, thehuman subject is a human SMA patient. In one embodiment, the compound isa compound of Formula (I) or a form thereof.

In another aspect, provided herein is a method for enhancing theinclusion of exon 7 of SMN1 and SMN2 into mRNA that is transcribed fromthe SMN1 and SMN2 genes in a human subject in need thereof, comprisingadministering to the human subject an effective amount a compound ofFormula (I) or a form thereof. In a particular embodiment, the compoundof Formula (I) or a form thereof enhances the inclusion of exon 7 ofSMN1 into mRNA that is transcribed from the SMN1 gene in an assay(s)described in International Publication No. WO2009/151546 or U.S. PatentApplication Publication No. 2011/0086833 (see, e.g., the Examples inthose publications), each of which is incorporated herein by referencein its entirety. In specific embodiments, the effective amount of thecompound of Formula (I) or a form thereof is administered to the humansubject in a pharmaceutical composition comprising a pharmaceuticallyacceptable carrier, excipient or diluent. In a specific embodiment, thehuman subject is a human SMA patient. In another specific embodiment,the human subject is a human SMA patient, wherein SMA is caused by aninactivating mutation or deletion in the SMN1 gene on both chromosomes,resulting in a loss of SMN1 gene function. In one embodiment, thecompound is a compound of Formula (I) or a form thereof.

In another aspect, provided herein are methods for enhancing theexpression of Smn protein in a human subject in need thereof, comprisingadministering to the human subject an effective amount of a compound ofFormula (I) or a form thereof. In a specific embodiment, provided hereinis a method for enhancing the expression of Smn protein in a humansubject in need thereof, comprising administering to the human subjectan effective amount a compound of Formula (I) or a form thereof thatenhances the inclusion of exon 7 of SMN2 into mRNA that is transcribedfrom the SMN2 gene. In another specific embodiment, provided herein is amethod for enhancing the expression of Smn protein in a human subject inneed thereof, comprising administering to the human subject an effectiveamount a compound of Formula (I) or a form thereof that enhances theinclusion of exon 7 of SMN1 and/or SMN2 into mRNA that is transcribedfrom the SMN1 and/or SMN2 gene. In specific embodiments, the effectiveamount of the compound of Formula (I) or a form thereof is administeredto the human subject in a pharmaceutical composition comprising apharmaceutically acceptable carrier, excipient or diluent. In aparticular embodiment, the compound of Formula (I) or a form thereofenhances the inclusion of exon 7 of SMN1 and/or SMN2 into mRNA that istranscribed from the SMN1 and/or SMN2 gene in an assay described herein(see, e.g., the Biological Examples, infra) or in InternationalPublication No. WO2009/151546 or U.S. Patent Application Publication No.2011/0086833 (see, e.g., the Examples in those publications), each ofwhich is incorporated herein by reference in its entirety.

In a specific embodiment, the human subject is a human SMA patient. Inanother specific embodiment, the human subject is a human SMA patient,wherein SMA is caused by an inactivating mutation or deletion in theteleomeric copy of the SMN1 gene in both chromosomes, resulting in aloss of SMN1 gene function. In one embodiment, the compound is acompound of Formula (I) or a form thereof.

In another embodiment, provided herein is the use of a compound ofFormula (I) or a form thereof for the preparation of a medicament thatenhances expression of Smn protein in a human subject in need thereof.In a particular embodiment, the compound of Formula (I) or a formthereof enhances the inclusion of exon 7 of SMN2 into mRNA that istranscribed from the SMN2 gene as determined in an assay describedherein (see, e.g., the Biological Examples, infra). In anotherembodiment, the compound of Formula (I) or a form thereof enhances theinclusion of exon 7 of SMN1 and/or SMN2 into mRNA that is transcribedfrom the SMN1 and/or SMN2 gene as determined in an assay describedherein (see, e.g., the Biological Examples, infra) or in InternationalPublication No. WO2009/151546 or U.S. Patent Application Publication No.2011/0086833 (see, e.g., the Examples in those publications), each ofwhich is incorporated herein by reference in its entirety. In a specificembodiment, the compound is a compound of Formula (I) or a form thereof.

In another aspect, provided herein are methods for treating spinalmuscular atrophy (SMA), comprising administering to a subject aneffective amount of a compound of Formula (I) or a form thereof. In aspecific embodiment, provided herein is a method for treating SMA in ahuman subject in need thereof, comprising administering to the subjectan effective amount of a compound of Formula (I) or a form thereof. Inanother specific embodiment, provided herein is a method for treatingSMA in a human subject in need thereof, comprising administering to thesubject a pharmaceutical composition comprising an effective amount of acompound of Formula (I) or a form thereof, and a pharmaceuticallyacceptable carrier, excipient or diluent. In one embodiment, thecompound is a compound of Formula (I) or a form thereof.

In another embodiment, provided herein is a method for treating SMA in ahuman subject in need thereof, comprising administering to the subjectan effective amount of a compound of Formula (I) or a form thereof thatenhances the inclusion of exon 7 of SMN2 into mRNA that is transcribedfrom the SMN2 gene. In a specific embodiment, provided herein is amethod for treating SMA in a human subject in need thereof, comprisingadministering to the subject a pharmaceutical composition comprising aneffective amount of a compound of Formula (I) or a form thereof thatenhances the inclusion of exon 7 of SMN2 into mRNA that is transcribedfrom the SMN2 gene, and a pharmaceutically acceptable carrier, excipientor diluent. In another specific embodiment, provided herein is a methodfor treating SMA in a human subject in need thereof, comprisingadministering to the subject a pharmaceutical composition comprising aneffective amount of a compound of Formula (I) or a form thereof thatenhances the inclusion of exon 7 of SMN1 and/or SMN2 into mRNA that istranscribed from the SMN1 and/or SMN2 gene, and a pharmaceuticallyacceptable carrier, excipient or diluent. In a particular embodiment,the compound of Formula (I) or a form thereof enhances the inclusion ofexon 7 of SMN2 into mRNA that is transcribed from the SMN2 gene in anassay described herein (see, e.g., the Biological Examples, infra). Inanother embodiment, the compound of Formula (I) or a form thereofenhances the inclusion of exon 7 of SMN1 and/or SMN2 into mRNA that istranscribed from the SMN1 and/or SMN2 gene as determined in an assaydescribed herein (see, e.g., the Biological Examples, infra) or inInternational Publication No. WO2009/151546 or U.S. Patent ApplicationPublication No. 2011/0086833 (see, e.g., the Examples in thosepublications), each of which is incorporated herein by reference in itsentirety. In a specific embodiment, the compound is a compound ofFormula (I) or a form thereof.

In another embodiment, provided herein is the use of a compound ofFormula (I) or a form thereof in the manufacture of a medicament fortreating SMA in a human subject in need thereof. In a particularembodiment, the compound of Formula (I) or a form thereof enhances theinclusion of exon 7 of SMN2 into mRNA that is transcribed from the SMN2gene as determined in an assay described herein (see, e.g., theBiological Examples, infra). In another embodiment, the compound ofFormula (I) or a form thereof enhances the inclusion of exon 7 of SMN1and/or SMN2 into mRNA that is transcribed from the SMN1 and/or SMN2 geneas determined in an assay described herein (see, e.g., the BiologicalExamples, infra) or in International Publication No. WO2009/151546 orU.S. Patent Application Publication No. 2011/0086833 (see, e.g., theExamples in those publications), each of which is incorporated herein byreference in its entirety. In a specific embodiment, the compound is acompound of Formula (I) or a form thereof.

In an embodiment of a use or method provided herein, compounds ofFormula (I) or a form thereof are used in combination with one or moreadditional agents. A compound(s) of Formula (I) or a form thereof can beadministered to a subject or contacted with a cell prior to,concurrently with, or subsequent to administering to the subject orcontacting the cell with an additional agent(s). A compound(s) ofFormula (I) or a form thereof and an additional agent(s) can beadministered to a subject or contacted with a cell in single compositionor different compositions. In a specific embodiments, a compound(s) ofFormula (I) or a form thereof is used in combination with genereplacement of SMN1 (using, e.g., viral delivery vectors). In anotherspecific embodiments, a compound(s) of Formula (I) or a form thereof areused in combination with cell replacement using differentiatedSMN1^(+/+) and/or SMN2^(+/+) stem cells. In another specificembodiments, a compound(s) of Formula (I) or a form thereof are used incombination with cell replacement using differentiated SMN1^(+/+) stemcells. In another specific embodiments, a compound(s) of Formula (I) ora form thereof are used in combination with cell replacement usingdifferentiated SMN2^(+/+) stem cells. In another specific embodiment, acompound(s) of Formula (I) or a form thereof are used in combinationwith aclarubicin. In another specific embodiment, a compound(s) ofFormula (I) or a form thereof are used in combination with atranscription activator such as a histone deacetylase (“HDAC”) inhibitor(e.g., butyrates, valproic acid, and hydroxyurea), and mRNA stabilizers(e.g., mRNA decapping inhibitor RG3039 from Repligen).

In one embodiment, provided herein is the use of compounds of Formula(I) or a form thereof in combination with supportive therapy, includingrespiratory, nutritional or rehabilitation care.

In certain embodiments, treating SMA with a compound of Formula (I) or aform thereof (alone or in combination with an additional agent) has atherapeutic effect and/or beneficial effect. In a specific embodiment,treating SMA with a compound of Formula (I) or a form thereof (alone orin combination with an additional agent) results in one, two or more ofthe following effects: (i) reduces or ameliorates the severity of SMA;(ii) delays onset of SMA; (iii) inhibits the progression of SMA; (iv)reduces hospitalization of a subject; (v) reduces hospitalization lengthfor a subject; (vi) increases the survival of a subject; (vii) improvesthe quality of life of a subject; (viii) reduces the number of symptomsassociated with SMA; (ix) reduces or ameliorates the severity of asymptom(s) associated with SMA; (x) reduces the duration of a symptomassociated with SMA; (xi) prevents the recurrence of a symptomassociated with SMA; (xii) inhibits the development or onset of asymptom of SMA; and/or (xiii) inhibits of the progression of a symptomassociated with SMA.

Symptoms of SMA include muscle weakness, poor muscle tone, weak cry,weak cough, limpness or a tendency to flop, difficulty sucking orswallowing, difficulty breathing, accumulation of secretions in thelungs or throat, clenched fists with sweaty hand, flickering/vibratingof the tongue, head often tilted to one side, even when lying down, legsthat tend to be weaker than the arms, legs frequently assuming a “froglegs” position, feeding difficulties, increased susceptibility torespiratory tract infections, bowel/bladder weakness, lower-than-normalweight, inability to sit without support, failure to walk, failure tocrawl, and hypotonia, areflexia, and multiple congenital contractures(arthrogryposis) associated with loss of anterior horn cells.

In a specific embodiment, treating SMA with a compound of Formula (I) ora form thereof (alone or in combination with an additional agent)results in one, two or more of the following effects: (i) a reduction inthe loss of muscle strength; (ii) an increase in muscle strength; (iii)a reduction in muscle atrophy; (iv) a reduction in the loss of motorfunction; (v) an increase in motor neurons; (vii) a reduction in theloss of motor neurons; (viii) protection of SMN deficient motor neuronsfrom degeneration; (ix) an increase in motor function; (x) an increasein pulmonary function; and/or (xi) a reduction in the loss of pulmonaryfunction.

In another embodiment, treating SMA with a compound of Formula (I) or aform thereof (alone or in combination with an additional agent) resultsin the functional ability or helps retain the functional ability for ahuman infant or a human toddler to sit up. In another embodiment,treating SMA with a compound of Formula (I) or a form thereof (alone orin combination with an additional agent) results in the functionalability or helps retain the functional ability for a human infant, ahuman toddler, a human child or a human adult to stand up unaided. Inanother embodiment, treating SMA with a compound of Formula (I) or aform thereof (alone or in combination with an additional agent) resultsin the functional ability or helps retain the functional ability for ahuman infant, a human toddler, a human child or a human adult to walkunaided. In another embodiment, treating SMA with a compound of Formula(I) or a form thereof (alone or in combination with an additional agent)results in the functional ability or helps retain the functional abilityfor a human infant, a human toddler, a human child or a human adult torun unaided. In another embodiment, treating SMA with a compound ofFormula (I) or a form thereof (alone or in combination with anadditional agent) results in the functional ability or helps retain thefunctional ability for a human infant, a human toddler, a human child ora human adult to breathe unaided. In another embodiment, treating SMAwith a compound of Formula (I) or a form thereof (alone or incombination with an additional agent) results in the functional abilityor helps retain the functional ability for a human infant, a humantoddler, a human child or a human adult to turn during sleep unaided. Inanother embodiment, treating SMA with a compound of Formula (I) or aform thereof (alone or in combination with an additional agent) resultsin the functional ability or helps retain the functional ability for ahuman infant, a human toddler, a human child or a human adult to swallowunaided.

In certain embodiments, a primer and/or probe described below in theBiological Examples (e.g., SMN primers such as SEQ ID NO. 1, 7, 8, 11 or13 and/or SEQ ID NO. 2, 9 or 12, and SMN probes such as a SEQ ID NO. 3or 10) is used in an assay, such as RT-PCR, RT-qPCR, endpoint RT-PCR,PCR, qPCR, rolling circle amplification, Northern blot or Southern blot,to determine whether a compound of Formula (I) or a form thereofenhances the inclusion of exon 7 of SMN1 and/or SMN2 into mRNA that istranscribed from an SMN1 and/or SMN2 gene. In some embodiments, a primerand/or probe described below in the Biological Examples (e.g., SMNprimers such as SEQ ID NO. 1, 7, 8, 11 or 13 and/or SEQ ID NO. 2, 9 or12, and SMN probes such as a SEQ ID NO. 3 or 10) is used in an assay,such as RT-PCR, RT-qPCR, endpoint RT-PCR, PCR, qPCR, rolling circleamplification, Northern blot or Southern blot, or a pharmaceutical orassay kit as described infra, to monitor patient responses to a compoundof Formula (I) or a form thereof.

In one embodiment, a compound of Formula (I):

-   -   or a form thereof is used as described herein, wherein:    -   w₁ and w₅ are independently C—R_(a) or N;    -   w₂ is C—R_(b) or N;    -   w₃, w₄ and w₇ are independently C—R₁, C—R₂, C—R_(a) or N;    -   w₆ is C—R₁, C—R₂, C—R_(c) or N;    -   wherein one of w₃, w₄, w₆ and w₇ is C—R₁ and one other of w₃,        w₄, w₆ and w₇ is C—R₂, provided that,    -   when w₃ is C—R₁, then w₆ is C—R₂ and w₄ and w₇ are independently        C—R_(a) or N; or,    -   when w₃ is C—R₂, then w₆ is C—R₁ and w₄ and w₇ are independently        C—R_(a) or N; or,    -   when w₄ is C—R₁, then w₇ is C—R₂ and w₃ is C—R_(a) or N and w₆        is C—R_(c) or N; or,    -   when w₄ is C—R₂, then w₇ is C—R₁ and w₃ is C—R_(a) or N and w₆        is C—R_(c) or N; and,    -   wherein any one, two or three of w₁, w₂, w₃, w₄, w₅, w₆ and w₇        may optionally be N;    -   R₁ is C₁₋₈alkyl, amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino,        C₁₋₈alkoxy-C₁₋₈alkyl-amino, (C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino,        (C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino, amino-C₁₋₈alkyl,        C₁₋₈alkyl-amino-C₁₋₈alkyl, (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        (C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl,        amino-C₁₋₈alkyl-amino, (amino-C₁₋₈alkyl)₂-amino,        (amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        C₁₋₈alkyl-amino-C₁₋₈alkyl-amino,        (C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,        (C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,        [(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,        amino-C₁₋₈alkoxy, C₁₋₈alkyl-amino-C₁₋₈alkoxy,        (C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,        C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,        C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,        (C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkoxy,        amino-C₂₋₈alkenyl, C₁₋₈alkyl-amino-C₂₋₈alkenyl,        (C₁₋₈alkyl)₂-amino-C₂₋₈alkenyl, amino-C₂₋₈alkynyl,        C₁₋₈alkyl-amino-C₂₋₈alkynyl, (C₁₋₈alkyl)₂-amino-C₂₋₈alkynyl,        halo-C₁₋₈alkyl-amino, (halo-C₁₋₈alkyl)₂-amino,        (halo-C₁₋₈alkyl)(C₁₋₈alkyl)amino, hydroxy-C₁₋₈alkyl,        hydroxy-C₁₋₈alkoxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkyl-amino,        (hydroxy-C₁₋₈alkyl)₂-amino, (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl,        hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,        (hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,        (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkoxy,        hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl-amino,        (hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,        (hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,        (hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl-amino,        [(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,        [(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,        heterocyclyl, heterocyclyl-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkoxy,        heterocyclyl-amino, (heterocyclyl)(C₁₋₈alkyl)amino,        heterocyclyl-amino-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkyl-amino,        (heterocyclyl-C₁₋₈alkyl)₂-amino,        (heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        heterocyclyl-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (heterocyclyl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        (heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl,        heterocyclyl-oxy, heterocyclyl-carbonyl,        heterocyclyl-carbonyl-oxy, C₃₋₁₄cycloalkyl,        aryl-C₁₋₈alkyl-amino, (aryl-C₁₋₈alkyl)₂-amino,        (aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        aryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (aryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        (aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, heteroaryl,        heteroaryl-C₁₋₈alkyl, heteroaryl-C₁₋₈alkoxy, heteroaryl-amino,        heteroaryl-C₁₋₈alkyl-amino, (heteroaryl-C₁₋₈alkyl)₂-amino,        (heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        heteroaryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (heteroaryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl or        (heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl;    -   wherein, each instance of heterocyclyl, C₃₋₁₄cycloalkyl, aryl        and heteroaryl is optionally substituted with one, two or three        R₃ substituents and optionally, with one additional R₄        substituent; or,    -   wherein, each instance of heterocyclyl, C₃₋₁₄cycloalkyl, aryl        and heteroaryl is optionally substituted with one, two, three or        four R₃ substituents;    -   R₂ is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl,        heteroaryl or heteroaryl-amino;    -   wherein, each instance of aryl, heterocyclyl and heteroaryl is        optionally substituted with one, two or three R₆ substituents        and optionally, with one additional R₇ substituent;    -   R_(a) is, in each instance, independently selected from        hydrogen, halogen or C₁₋₈alkyl;    -   R_(b) is hydrogen, halogen, C₁₋₈alkyl or C₁₋₈alkoxy;    -   R₃ is, in each instance, independently selected from cyano,        halogen, hydroxy, oxo, C₁₋₈alkyl, halo-C₁₋₈alkyl,        C₁₋₈alkyl-carbonyl, C₁₋₈alkoxy, halo-C₁₋₈alkoxy,        C₁₋₈alkoxy-C₁₋₈alkyl, C₁₋₈alkoxy-carbonyl, amino,        C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino, amino-C₁₋₈alkyl,        C₁₋₈alkyl-amino-C₁₋₈alkyl, (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        amino-C₁₋₈alkyl-amino, C₁₋₈alkyl-amino-C₁₋₈alkyl-amino,        (C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,        (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,        [(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl]₂-amino,        (C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        [(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,        C₁₋₈alkoxy-C₁₋₈alkyl-amino, (C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino,        (C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        C₁₋₈alkyl-carbonyl-amino, C₁₋₈alkoxy-carbonyl-amino,        hydroxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkoxy-C₁₋₈alkyl,        hydroxy-C₁₋₈alkyl-amino, (hydroxy-C₁₋₈alkyl)₂-amino or        (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino;    -   R₄ is C₃₋₁₄cycloalkyl, C₃₋₁₄cycloalkyl-C₁₋₈alkyl,        C₃₋₁₄cycloalkyl-amino, aryl-C₁₋₈alkyl, aryl-C₁₋₈alkoxy-carbonyl,        aryl-sulfonyloxy-C₁₋₈alkyl, heterocyclyl or        heterocyclyl-C₁₋₈alkyl; wherein, each instance of        C₃₋₁₄cycloalkyl, aryl and heterocyclyl is optionally substituted        with one, two or three R₅ substituents;    -   R₅ is, in each instance, independently selected from halogen,        hydroxy, cyano, nitro, C₁₋₈alkyl, halo-C₁₋₈alkyl, C₁₋₈alkoxy,        halo-C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino or        C₁₋₈alkyl-thio;    -   R₆ is, in each instance, independently selected from halogen,        hydroxy, cyano, nitro, C₁₋₈alkyl, C₂₋₈alkenyl, halo-C₁₋₈alkyl,        hydroxy-C₁₋₈alkyl, C₁₋₈alkoxy, halo-C₁₋₈alkoxy,        C₁₋₈alkoxy-C₁₋₈alkyl, amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino        or C₁₋₈alkyl-thio; and,    -   R₇ is C₃₋₁₄cycloalkyl, C₃₋₁₄cycloalkyl-oxy, aryl, heterocyclyl        or heteroaryl.

An embodiment of the use of the compound of Formula (I) is the use of acompound selected from Formula (II), Formula (III), Formula (IV),Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX),Formula (X), Formula (XI), Formula (XII), Formula (XIII) or Formula(XIV):

or a form thereof.

In an embodiment of the use of the compound of Formula (I), w₃ is C—R₁,w₆ is C—R₂, w₁, w₄, w₅ and w₇ are independently C—R_(a) or N and w₂ isC—R_(b) or N.

In another embodiment of the use of the compound of Formula (I), w₃ isC—R₂, w₆ is C—R₁, w₁, w₄, w₅ and w₇ are independently C—R_(a) or N andw₂ is C—R_(b) or N.

In another embodiment of the use of the compound of Formula (I), w₄ isC—R₁, w₇ is C—R₂, w₁, w₃ and w₅ are independently C—R_(a) or N, w₂ isC—R_(b) or N and w₆ is C—R_(c) or N.

In another embodiment of the use of the compound of Formula (I), w₄ isC—R₂, w₇ is C—R₁, w₁, w₃ and w₅ are independently C—R_(a) or N, w₂ isC—R_(b) or N and w₆ is C—R_(c) or N.

In an embodiment of the use of the compound of Formula (II), w₃ is C—R₁,w₆ is C—R₂, w₄, w₅ and w₇ are independently C—R_(a) or N and w₂ isC—R_(b) or N.

In another embodiment of the use of the compound of Formula (II), w₃ isC—R₂, w₆ is C—R₁, w₄, w₅ and w₇ are independently C—R_(a) or N and w₂ isC—R_(b) or N.

In another embodiment of the use of the compound of Formula (II), w₄ isC—R₁, w₇ is C—R₂, w₃ and w₅ are independently C—R_(a) or N, w₂ isC—R_(b) or N and w₆ is C—R_(c) or N.

In another embodiment of the use of the compound of Formula (II), w₄ isC—R₂, w₇ is C—R₁, w₃ and w₅ are independently C—R_(a) or N, w₂ isC—R_(b) or N and w₆ is C—R_(c) or N.

In an embodiment of the use of the compound of Formula (III), w₃ isC—R₁, w₆ is C—R₂ and w₁, w₄, w₅ and w₇ are independently C—R_(a) or N.

In another embodiment of the use of the compound of Formula (III), w₃ isC—R₂, w₆ is C—R₁ and w₁, w₄, w₅ and w₇ are independently C—R_(a) or N.

In another embodiment of the use of the compound of Formula (III), w₄ isC—R₁, w₇ is C—R₂, w₁, w₃ and w₅ are independently C—R_(a) or N and w₆ isC—R_(c) or N.

In another embodiment of the use of the compound of Formula (III), w₄ isC—R₂, w₇ is C—R₁, w₁, w₃ and w₅ are independently C—R_(a) or N and w₆ isC—R_(c) or N.

In an embodiment of the use of the compound of Formula (IV), w₄ is C—R₁,w₇ is C—R₂, w₁ and w₅ are independently C—R_(a) or N, w₂ is C—R_(b) or Nand w₆ is C—R_(c) or N.

In another embodiment of the use of the compound of Formula (IV), w₄ isC—R₂, w₇ is C—R₁, w₁ and w₅ are independently C—R_(a) or N, w₂ isC—R_(b) or N and w₆ is C—R_(c) or N.

In an embodiment of the use of the compound of Formula (V), w₃ is C—R₁,w₆ is C—R₂, w₁, w₅ and w₇ are independently C—R_(a) or N and w₂ isC—R_(b) or N.

In another embodiment of the use of the compound of Formula (V), w₃ isC—R₂, w₆ is C—R₁, w₁, w₅ and w₇ are independently C—R_(a) or N and w₂ isC—R_(b) or N.

In an embodiment of the use of the compound of Formula (VI), w₃ is C—R₁,w₆ is C—R₂, w₁, w₄ and w₇ are independently C—R_(a) or N and w₂ isC—R_(b) or N.

In another embodiment of the use of the compound of Formula (VI), w₃ isC—R₂, w₆ is C—R₁, w₁, w₄ and w₇ are independently C—R_(a) or N and w₂ isC—R_(b) or N.

In another embodiment of the use of the compound of Formula (VI), w₄ isC—R₁, w₇ is C—R₂, w₁ and w₃ are independently C—R_(a) or N, w₂ isC—R_(b) or N and w₆ is C—R_(c) or N.

In another embodiment of the use of the compound of Formula (VI), w₄ isC—R₂, w₇ is C—R₁, w₁ and w₃ are independently C—R_(a) or N, w₂ isC—R_(b) or N and w₆ is C—R_(c) or N.

In another embodiment of the use of the compound of Formula (VII), w₄ isC—R₁, w₇ is C—R₂, w₁, w₃ and w₅ are C—R_(a) or N and w₂ is C—R_(b) or N.

In another embodiment of the use of the compound of Formula (VII), w₄ isC—R₂, w₇ is C—R₁, w₁, w₃ and w₅ are C—R_(a) or N and w₂ is C—R_(b) or N.

In another embodiment of the use of the compound of Formula (VIII), w₃is C—R₁, w₆ is C—R₂, w₁, w₄ and w₅ are C—R_(a) or N and w₂ is C—R_(b) orN.

In another embodiment of the use of the compound of Formula (VIII), w₃is C—R₂, w₆ is C—R₁, w₁, w₄ and w₅ are C—R_(a) or N and w₂ is C—R_(b) orN.

In an embodiment of the use of the compound of Formula (IX), w₃ is C—R₁,w₆ is C—R₂, w₄ and w₇ are independently C—R_(a) or N and w₂ is C—R_(b)or N.

In another embodiment of the use of the compound of Formula (IX), w₃ isC—R₂, w₆ is C—R₁, w₄ and w₇ are independently C—R_(a) or N and w₂ isC—R_(b) or N.

In another embodiment of the use of the compound of Formula (IX), w₄ isC—R₁, w₇ is C—R₂, w₂ is C—R_(b) or N, w₃ is C—R_(a) or N and w₆ isC—R_(c) or N.

In another embodiment of the use of the compound of Formula (IX), w₄ isC—R₂, w₇ is C—R₁, w₂ is C—R_(b) or N, w₃ is C—R_(a) or N and w₆ isC—R_(c) or N.

In an embodiment of the use of the compound of Formula (X), w₃ is C—R₁,w₆ is C—R₂, w₂ is C—R_(b) or N and w₅ and w₇ are independently C—R_(a)or N.

In another embodiment of the use of the compound of Formula (X), w₃ isC—R₂, w₆ is C—R₁, w₂ is C—R_(b) or N and w₅ and w₇ are independentlyC—R_(a) or N.

In an embodiment of the use of the compound of Formula (XI), w₄ is C—R₁,w₇ is C—R₂, w₂ is C—R_(b) or N, w₅ is C—R_(a) or N and w₆ is C—R_(c) orN.

In another embodiment of the use of the compound of Formula (XI), w₄ isC—R₂, w₇ is C—R₁, w₂ is C—R_(b) or N, w₅ is C—R_(a) or N and w₆ isC—R_(c) or N.

In an embodiment of the use of the compound of Formula (XII), w₃ isC—R₁, w₆ is C—R₂ and w₄, w₅ and w₇ are independently C—R_(a) or N.

In another embodiment of the use of the compound of Formula (XII), w₃ isC—R₂, w₆ is C—R₁ and w₄, w₅ and w₇ are independently C—R_(a) or N.

In another embodiment of the use of the compound of Formula (XII), w₄ isC—R₁, w₇ is C—R₂, w₃ and w₅ are independently C—R_(a) or N and w₆ isC—R_(c) or N.

In another embodiment of the use of the compound of Formula (XII), w₄ isC—R₂, w₇ is C—R₁, w₃ and w₅ are independently C—R_(a) or N and w₆ isC—R_(c) or N.

In an embodiment of the use of the compound of Formula (XIII), w₃ isC—R₁, w₆ is C—R₂, w₂ is C—R_(b) or N and w₄ and w₅ are independentlyC—R_(a) or N.

In another embodiment of the use of the compound of Formula (XIII), w₃is C—R₂, w₆ is C—R₁, w₂ is C—R_(b) or N and w₄ and w₅ are independentlyC—R_(a) or N.

In an embodiment of the use of the compound of Formula (XIV), w₄ isC—R₁, w₇ is C—R₂, w₂ is C—R_(b) or N and w₃ and w₅ are independentlyC—R_(a) or N.

In another embodiment of the use of the compound of Formula (XIV), w₄ isC—R₂, w₇ is C—R₁, w₂ is C—R_(b) or N and w₃ and w₅ are independentlyC—R_(a) or N.

Another embodiment of the use of the compound of Formula (I) is the useof the compound selected from Formula (II), Formula (III), Formula (IX),Formula (XI) or Formula (XII):

or a form thereof.

Another embodiment of the use of the compound of Formula (I) is the useof the compound of Formula (II):

or a form thereof.

Another embodiment of the use of the compound of Formula (I) is the useof the compound of Formula (III):

or a form thereof.

Another embodiment of the use of the compound of Formula (I) is the useof the compound of Formula (IV):

or a form thereof.

Another embodiment of the use of the compound of Formula (I) is the useof the compound of Formula (V):

or a form thereof.

Another embodiment of the use of the compound of Formula (I) is the useof the compound of Formula (VI):

or a form thereof.

Another embodiment of the use of the compound of Formula (I) is the useof the compound of Formula (VII):

or a form thereof.

Another embodiment of the use of the compound of Formula (I) is the useof the compound of Formula (VIII):

or a form thereof.

Another embodiment of the use of the compound of Formula (I) is the useof the compound of Formula (IX):

or a form thereof.

Another embodiment of the use of the compound of Formula (I) is the useof the compound of Formula (X):

or a form thereof.

Another embodiment of the use of the compound of Formula (I) is the useof the compound of Formula (XI):

or a form thereof.

Another embodiment of the compound of Formula (I) is the use of thecompound of Formula (XII):

or a form thereof.

Another embodiment of the use of the compound of Formula (I) is the useof the compound of Formula (XIII):

or a form thereof.

Another embodiment of the use of the compound of Formula (I) is the useof the compound of Formula (XIV):

or a form thereof.

An embodiment of the use of the compound of Formula (I), Formula (II),Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII),Formula (VIII), Formula (IX), Formula (X), Formula (XI), Formula (XII),Formula (XIII) or Formula (XIV) is the use of a compound selected fromFormula (Ia), Formula (IIa), Formula (IIIa), Formula (IVa), Formula(Va), Formula (VIa), Formula (VIIa), Formula (VIIIa), Formula (IXa),Formula (Xa), Formula (XIa), Formula (XIIa), Formula (XIIIa) or Formula(XIVa), respectively:

or a form thereof.

In an embodiment of the use of the compound of Formula (Ia), one of w₃,w₄, w₆ and w₇ is C—R₁ and one other of w₃, w₄, w₆ and w₇ is C—R₂,provided that,

when w₃ is C—R₁, then w₆ is C—R₂ and w₄ and w₇ are independently C—R_(a)or N; or,

when w₃ is C—R₂, then w₆ is C—R₁ and w₄ and w₇ are independently C—R_(a)or N; or,

when w₄ is C—R₁, then w₇ is C—R₂ and w₃ is C—R_(a) or N and w₆ isC—R_(c) or N; or,

when w₄ is C—R₂, then w₇ is C—R₁ and w₃ is C—R_(a) or N and w₆ isC—R_(c) or N.

In an embodiment of the use of the compound of Formula (IIa), one of w₃,w₄, w₆ and w₇ is C—R₁ and one other of w₃, w₄, w₆ and w₇ is C—R₂,provided that,

when w₃ is C—R₁, then w₆ is C—R₂ and w₄ and w₇ are independently C—R_(a)or N; or,

when w₃ is C—R₂, then w₆ is C—R₁ and w₄ and w₇ are independently C—R_(a)or N; or,

when w₄ is C—R₁, then w₇ is C—R₂ and w₃ is C—R_(a) or N and w₆ isC—R_(c) or N; or,

when w₄ is C—R₂, then w₇ is C—R₁ and w₃ is C—R_(a) or N and w₆ isC—R_(c) or N.

In an embodiment of the use of the compound of Formula (IIIa), one ofw₃, w₄, w₆ and w₇ is C—R₁ and one other of w₃, w₄, w₆ and w₇ is C—R₂,provided that,

when w₃ is C—R₁, then w₆ is C—R₂ and w₄ and w₇ are independently C—R_(a)or N; or,

when w₃ is C—R₂, then w₆ is C—R₁ and w₄ and w₇ are independently C—R_(a)or N; or,

when w₄ is C—R₁, then w₇ is C—R₂ and w₃ is C—R_(a) or N and w₆ isC—R_(c) or N; or,

when w₄ is C—R₂, then w₇ is C—R₁ and w₃ is C—R_(a) or N and w₆ isC—R_(c) or N.

In an embodiment of the use of the compound of Formula (IVa), one of w₄and w₇ is C—R₁ and the other is C—R₂, provided that, when w₄ is C—R₁,then w₇ is C—R₂; or, when w₄ is C—R₂, then w₇ is C—R₁.

In an embodiment of the use of the compound of Formula (Va), one of w₃and w₆ is C—R₁ and the other is C—R₂, provided that, when w₃ is C—R₁,then w₆ is C—R₂; or, when w₃ is C—R₂, then w₆ is C—R₁.

In an embodiment of the use of the compound of Formula (VIa), one of w₃,w₄, w₆ and w₇ is C—R₁ and one other of w₃, w₄, w₆ and w₇ is C—R₂,provided that,

when w₃ is C—R₁, then w₆ is C—R₂ and w₄ and w₇ are independently C—R_(a)or N; or,

when w₃ is C—R₂, then w₆ is C—R₁ and w₄ and w₇ are independently C—R_(a)or N; or,

when w₄ is C—R₁, then w₇ is C—R₂ and w₃ is C—R_(a) or N and w₆ isC—R_(c) or N; or,

when w₄ is C—R₂, then w₇ is C—R₁ and w₃ is C—R_(a) or N and w₆ isC—R_(c) or N.

In an embodiment of the use of the compound of Formula (VIIa), one of w₄and w₇ is C—R₁ and the other is C—R₂, provided that, when w₄ is C—R₁,then w₇ is C—R₂; or, when w₄ is C—R₂, then w₇ is C—R₁.

In an embodiment of the use of the compound of Formula (VIIIa), one ofw₃ and w₆ is C—R₁ and the other is C—R₂, provided that, when w₃ is C—R₁,then w₆ is C—R₂; or, when w₃ is C—R₂, then w₆ is C—R₁.

In an embodiment of the use of the compound of Formula (IXa), one of w₃,w₄, w₆ and w₇ is C—R₁ and one other of w₃, w₄, w₆ and w₇ is C—R₂,provided that,

when w₃ is C—R₁, then w₆ is C—R₂ and w₄ and w₇ are independently C—R_(a)or N; or,

when w₃ is C—R₂, then w₆ is C—R₁ and w₄ and w₇ are independently C—R_(a)or N; or,

when w₄ is C—R₁, then w₇ is C—R₂ and w₃ is C—R_(a) or N and w₆ isC—R_(c) or N; or,

when w₄ is C—R₂, then w₇ is C—R₁ and w₃ is C—R_(a) or N and w₆ isC—R_(c) or N.

In an embodiment of the use of the compound of Formula (Xa), one of w₃and w₆ is C—R₁ and the other is C—R₂, provided that, when w₃ is C—R₁,then w₆ is C—R₂; or, when w₃ is C—R₂, then w₆ is C—R₁.

In an embodiment of the use of the compound of Formula (XIa), one of w₄and w₇ is C—R₁ and the other is C—R₂, provided that, when w₄ is C—R₁,then w₇ is C—R₂; or, when w₄ is C—R₂, then w₇ is C—R₁.

In an embodiment of the use of the compound of Formula (XIIa), one ofw₃, w₄, w₆ and w₇ is C—R₁ and one other of w₃, w₄, w₆ and w₇ is C—R₂,provided that,

when w₃ is C—R₁, then w₆ is C—R₂ and w₄ and w₇ are independently C—R_(a)or N; or,

when w₃ is C—R₂, then w₆ is C—R₁ and w₄ and w₇ are independently C—R_(a)or N; or,

when w₄ is C—R₁, then w₇ is C—R₂ and w₃ is C—R_(a) or N and w₆ isC—R_(c) or N; or,

when w₄ is C—R₂, then w₇ is C—R₁ and w₃ is C—R_(a) or N and w₆ isC—R_(c) or N.

In an embodiment of the use of the compound of Formula (XIIIa), one ofw₃ and w₆ is C—R₁ and the other is C—R₂, provided that, when w₃ is C—R₁,then w₆ is C—R₂; or, when w₃ is C—R₂, then w₆ is C—R₁.

In an embodiment of the use of the compound of Formula (XIVa), one of w₄and w₇ is C—R₁ and the other is C—R₂, provided that, when w₄ is C—R₁,then w₇ is C—R₂; or, when w₄ is C—R₂, then w₇ is C—R₁.

An embodiment of the use of the compound of Formula (I), Formula (II),Formula (III), Formula (IX), Formula (XI) or Formula (XII) is the use ofthe compound selected from Formula (Ia), Formula (IIa), Formula (IIIa),Formula (IXa), Formula (XIa) or Formula (XIIa), respectively:

or a form thereof.

Another embodiment of the use of the compound of Formula (I) is the useof the compound of Formula (Ia):

or a form thereof.

Another embodiment of the use of the compound of Formula (II) is the useof the compound of Formula (IIa):

or a form thereof.

Another embodiment of the use of the compound of Formula (III) is theuse of the compound of Formula (IIIa):

or a form thereof.

Another embodiment of the use of the compound of Formula (IV) is the useof the compound of Formula (IVa):

or a form thereof.

Another embodiment of the use of the compound of Formula (V) is the useof the compound of Formula (Va):

or a form thereof.

Another embodiment of the use of the compound of Formula (VI) is the useof the compound of Formula (VIa):

or a form thereof.

Another embodiment of the use of the compound of Formula (VII) is theuse of the compound of Formula (VIIa):

or a form thereof.

Another embodiment of the use of the compound of Formula (VIII) is theuse of the compound of Formula (VIIIa):

or a form thereof.

Another embodiment of the use of the compound of Formula (IX) is the useof the compound of Formula (IXa):

or a form thereof.

Another embodiment of the use of the compound of Formula (X) is the useof the compound of Formula (Xa):

or a form thereof.

Another embodiment of the use of the compound of Formula (XI) is the useof the compound of Formula (XIa):

or a form thereof.

Another embodiment of the use of the compound of Formula (XII) is theuse of the compound of Formula (XIIa):

or a form thereof.

Another embodiment of the use of the compound of Formula (XIII) is theuse of the compound of Formula (XIIIa):

or a form thereof.

Another embodiment of the use of the compound of Formula (XIV) is theuse of the compound of Formula (XIVa):

or a form thereof.

An embodiment of the use of the compound of Formula (Ia) is the use of acompound of Formula (Ia1), Formula (Ia2), Formula (Ia3) or Formula(Ia4):

or a form thereof.

An embodiment of the use of the compound of Formula (IIa) is the use ofa compound of Formula (IIa1), Formula (IIa2), Formula (IIa3) or Formula(IIa4):

or a form thereof.

An embodiment of the use of the compound of Formula (IIIa) is the use ofa compound of Formula (IIIa1), Formula (IIIa2), Formula (IIIa3) orFormula (IIIa4):

or a form thereof.

An embodiment of the use of the compound of Formula (IVa) is the use ofa compound of Formula (IVa1) or Formula (IVa2):

or a form thereof.

An embodiment of the use of the compound of Formula (Va) is the use of acompound of Formula (Va1) or Formula (Va2):

or a form thereof.

An embodiment of the use of the compound of Formula (VIa) is the use ofa compound of Formula (VIa1), Formula (VIa2), Formula (VIa3) or Formula(VIa2):

or a form thereof.

An embodiment of the use of the compound of Formula (VIIa) is the use ofa compound of Formula (VIIa1) or Formula (VIIa2):

or a form thereof.

An embodiment of the use of the compound of Formula (VIIIa) is the useof a compound of Formula (VIIIa1) or Formula (VIIIa2):

or a form thereof.

An embodiment of the use of the compound of Formula (IXa) is the use ofa compound of Formula (IXa1), Formula (IXa2), Formula (IXa3) or Formula(IXa4):

or a form thereof.

An embodiment of the use of the compound of Formula (Xa) is the use of acompound of Formula (Xa1) or Formula (Xa2):

or a form thereof.

An embodiment of the use of the compound of Formula (XIa) is the use ofa compound of Formula (XIa1) or Formula (XIa2):

or a form thereof.

An embodiment of the use of the compound of Formula (XIIa) is the use ofa compound of Formula (XIIa1), Formula (XIIa2), Formula (XIIa3) orFormula (XIIa4):

or a form thereof.

An embodiment of the use of the compound of Formula (XIIIa) is the useof a compound of Formula (XIIIa1) or Formula (XIIIa2):

or a form thereof.

An embodiment of the use of the compound of Formula (XIVa) is the use ofa compound of Formula (XIVa1) or Formula (XIVa2):

or a form thereof.

An embodiment of the use of the compound of Formula (Ia) is the use ofthe compound of Formula (Ia1):

or a form thereof.

An embodiment of the use of the compound of Formula (Ia) is the use ofthe compound of Formula (Ia2):

or a form thereof.

An embodiment of the use of the compound of Formula (Ia) is the use ofthe compound of Formula (Ia3):

or a form thereof.

An embodiment of the use of the compound of Formula (Ia) is the use ofthe compound of Formula (Ia4):

or a form thereof.

An embodiment of the use of the compound of Formula (IIa) is the use ofthe compound of Formula (IIa1):

or a form thereof.

An embodiment of the use of the compound of Formula (IIa) is the use ofthe compound of Formula (IIa2):

or a form thereof.

An embodiment of the use of the compound of Formula (IIa) is the use ofthe compound of Formula (IIa3):

or a form thereof.

An embodiment of the use of the compound of Formula (IIa) is the use ofthe compound of Formula (IIa4):

or a form thereof.

An embodiment of the use of the compound of Formula (IIIa) is the use ofthe compound of Formula (IIIa1):

or a form thereof.

An embodiment of the use of the compound of Formula (IIIa) is the use ofthe compound of Formula (IIIa2):

or a form thereof.

An embodiment of the use of the compound of Formula (IIIa) is the use ofthe compound of Formula (IIIa3):

or a form thereof.

An embodiment of the use of the compound of Formula (IIIa) is the use ofthe compound of Formula (IIIa4):

or a form thereof.

An embodiment of the use of the compound of Formula (IVa) is the use ofthe compound of Formula (IVa1):

or a form thereof.

An embodiment of the use of the compound of Formula (IVa) is the use ofthe compound of Formula (IVa2):

or a form thereof.

An embodiment of the use of the compound of Formula (Va) is the use ofthe compound of Formula (Va1):

or a form thereof.

An embodiment of the use of the compound of Formula (Va) is the use ofthe compound of Formula (Va2):

or a form thereof.

An embodiment of the use of the compound of Formula (VIa) is the use ofthe compound of Formula (VIa1):

or a form thereof.

An embodiment of the use of the compound of Formula (VIa) is the use ofthe compound of Formula (VIa2):

or a form thereof.

An embodiment of the use of the compound of Formula (VIa) is the use ofthe compound of Formula (VIa3):

or a form thereof.

An embodiment of the use of the compound of Formula (VIa) is the use ofthe compound of Formula (VIa4):

or a form thereof.

An embodiment of the use of the compound of Formula (VIIa) is the use ofthe compound of Formula (VIIa1):

or a form thereof.

An embodiment of the use of the compound of Formula (VIIa) is the use ofthe compound of Formula (VIIa2):

or a form thereof.

An embodiment of the use of the compound of Formula (VIIIa) is the useof the compound of Formula (VIIIa1):

or a form thereof.

An embodiment of the use of the compound of Formula (VIIIa) is the useof the compound of Formula (VIIIa2):

or a form thereof.

An embodiment of the use of the compound of Formula (IXa) is the use ofthe compound of Formula (IXa1):

or a form thereof.

An embodiment of the use of the compound of Formula (IXa) is the use ofthe compound of Formula (IXa2):

or a form thereof.

An embodiment of the use of the compound of Formula (IXa) is the use ofthe compound of Formula (IXa3):

or a form thereof.

An embodiment of the use of the compound of Formula (IXa) is the use ofthe compound of Formula (IXa4):

or a form thereof.

An embodiment of the use of the compound of Formula (Xa) is the use ofthe compound of Formula (Xa1):

or a form thereof.

An embodiment of the use of the compound of Formula (Xa) is the use ofthe compound of Formula (Xa2):

or a form thereof.

An embodiment of the use of the compound of Formula (XIa) is the use ofthe compound of Formula (XIa1):

or a form thereof.

An embodiment of the use of the compound of Formula (XIa) is the use ofthe compound of Formula (XIa2):

or a form thereof.

An embodiment of the use of the compound of Formula (XIIa) is the use ofthe compound of Formula (XIIa1):

or a form thereof.

An embodiment of the use of the compound of Formula (XIIa) is the use ofthe compound of Formula (XIIa2):

or a form thereof.

An embodiment of the use of the compound of Formula (XIIa) is the use ofthe compound of Formula (XIIa3):

or a form thereof.

An embodiment of the use of the compound of Formula (XIIa) is the use ofthe compound of Formula (XIIa4):

or a form thereof.

An embodiment of the use of the compound of Formula (XIIIa) is the useof the compound of Formula (XIIIa1):

or a form thereof.

An embodiment of the use of the compound of Formula (XIIIa) is the useof the compound of Formula (XIIIa2):

or a form thereof.

An embodiment of the use of the compound of Formula (XIVa) is the use ofthe compound of Formula (XIVa1):

or a form thereof.

An embodiment of the use of the compound of Formula (XIVa) is the use ofthe compound of Formula (XIVa2):

or a form thereof.

Patient Population

In some embodiments, a compound of Formula (I) or a form thereof, or apharmaceutical composition thereof is administered to a subjectsuffering from SMA. In other embodiments, a compound of Formula (I) or aform thereof, is administered to a subject predisposed or susceptible toSMA. In a specific embodiment, a compound of Formula (I) or a formthereof, or a pharmaceutical composition thereof is administered to ahuman subject having SMA, wherein SMA is caused by an inactivatingmutation or deletion in the SMN1 gene on both chromosomes, resulting ina loss of SMN1 gene function. In certain embodiments, the human subjectis genotyped prior to administration of a compound of Formula (I) or aform thereof, or a pharmaceutical composition thereof to determinewhether the subject has an inactivating mutation or deletion in theteleomeric copy of the SMN1 gene in both chromosomes, which results in aloss of SMN1 gene function. In some embodiments, a compound of Formula(I) or a form thereof, or pharmaceutical composition thereof isadministered to a subject with Type 0 SMA. In some embodiments, acompound of Formula (I) or a form thereof, or a pharmaceuticalcomposition thereof is administered to a subject with Type 1 SMA. Inother embodiments, a compound of Formula (I) or a form thereof, or apharmaceutical composition thereof is administered to a subject withType 2 SMA. In other embodiments, a compound of Formula (I) or a formthereof, or a pharmaceutical composition thereof is administered to asubject with Type 3 SMA. In some embodiments, a compound of Formula (I)or a form thereof, or a pharmaceutical composition thereof isadministered to a subject with Type 4 SMA. In certain embodiments, thehuman subject is an SMA patient.

In certain embodiments, a compound of Formula (I) or a form thereof, ora pharmaceutical composition thereof is administered to a subject thatwill or might benefit from enhanced inclusion of exon 7 of SMN1 and/orSMN2 into mRNA that is transcribed from the SMN1 and/or SMN2 gene. Inspecific embodiments, a compound of Formula (I) or a form thereof, or apharmaceutical composition thereof is administered to a subject thatwill or may benefit from enhanced Smn protein expression.

In certain embodiments, a compound of Formula (I) or a form thereof, ora pharmaceutical composition thereof is administered to a human that hasan age in a range of from about 0 months to about 6 months old, fromabout 6 to about 12 months old, from about 6 to about 18 months old,from about 18 to about 36 months old, from about 1 to about 5 years old,from about 5 to about 10 years old, from about 10 to about 15 years old,from about 15 to about 20 years old, from about 20 to about 25 yearsold, from about 25 to about 30 years old, from about 30 to about 35years old, from about 35 to about 40 years old, from about 40 to about45 years old, from about 45 to about 50 years old, from about 50 toabout 55 years old, from about 55 to about 60 years old, from about 60to about 65 years old, from about 65 to about 70 years old, from about70 to about 75 years old, from about 75 to about 80 years old, fromabout 80 to about 85 years old, from about 85 to about 90 years old,from about 90 to about 95 years old or from about 95 to about 100 yearsold.

In some embodiments, a compound of Formula (I) or a form thereof, or apharmaceutical composition thereof is administered to a human infant. Inother embodiments, a compound of Formula (I) or a form thereof, or apharmaceutical composition thereof is administered to a human toddler.In other embodiments, a compound of Formula (I) or a form thereof, or apharmaceutical composition thereof is administered to a human child. Inother embodiments, a compound of Formula (I) or a form thereof, or apharmaceutical composition thereof is administered to a human adult. Inyet other embodiments, a compound of Formula (I) or a form thereof, or apharmaceutical composition thereof is administered to an elderly human.

In some embodiments, a compound of Formula (I) or a form thereof, or apharmaceutical composition thereof, is administered to a patient toprevent the onset of SMA in a patient at risk of developing SMA. Inother embodiments, an effective amount of a compound of Formula (I) or aform thereof, or a pharmaceutical composition thereof, is administeredto a patient to prevent the onset of SMA in a patient at risk ofdeveloping SMA. In other embodiments, a prophylactically effectiveamount of a compound of Formula (I) or a form thereof, or apharmaceutical composition thereof, is administered to a patient toprevent the onset of SMA in a patient at risk of developing SMA. Inother embodiments, a therapeutically effective amount of a compound ofFormula (I) or a form thereof, or a pharmaceutical composition thereof,is administered to a patient to prevent the onset of SMA in a patient atrisk of developing SMA.

In some embodiments, a compound of Formula (I) or a form thereof, or apharmaceutical composition thereof, is administered to an SMA patient totreat or ameliorate SMA. In other embodiments, an effective amount of acompound of Formula (I) or a form thereof, or a pharmaceuticalcomposition thereof, is administered to an SMA patient to treat orameliorate SMA. In other embodiments, a prophylactically effectiveamount of a compound of Formula (I) or a form thereof, or apharmaceutical composition thereof, is administered to an SMA patient toprevent advancement of SMA. In other embodiments, a therapeuticallyeffective amount of a compound of Formula (I) or a form thereof, or apharmaceutical composition thereof, is administered to an SMA patient totreat or ameliorate SMA.

In some embodiments, a compound of Formula (I) or a form thereof, or amedicament thereof is administered to a subject suffering from SMA. Inother embodiments, a compound of Formula (I) or a form thereof, isadministered to a subject predisposed or susceptible to SMA. In aspecific embodiment, a compound of Formula (I) or a form thereof, or amedicament thereof is administered to a human subject having SMA,wherein SMA is caused by an inactivating mutation or deletion in theSMN1 gene on both chromosomes, resulting in a loss of SMN1 genefunction. In certain embodiments, the human subject is genotyped priorto administration of a compound of Formula (I) or a form thereof, or amedicament thereof to determine whether the subject has an inactivatingmutation or deletion in the teleomeric copy of the SMN1 gene in bothchromosomes, which results in a loss of SMN1 gene function. In someembodiments, a compound of Formula (I) or a form thereof, or medicamentthereof is administered to a subject with Type 0 SMA. In someembodiments, a compound of Formula (I) or a form thereof, or amedicament thereof is administered to a subject with Type 1 SMA. Inother embodiments, a compound of Formula (I) or a form thereof, or amedicament thereof is administered to a subject with Type 2 SMA. Inother embodiments, a compound of Formula (I) or a form thereof, or amedicament thereof is administered to a subject with Type 3 SMA. In someembodiments, a compound of Formula (I) or a form thereof, or amedicament thereof is administered to a subject with Type 4 SMA. Incertain embodiments, the human subject is an SMA patient.

In certain embodiments, a compound of Formula (I) or a form thereof, ora medicament thereof is administered to a subject that will or mightbenefit from enhanced inclusion of exon 7 of SMN1 and/or SMN2 into mRNAthat is transcribed from the SMN1 and/or SMN2 gene. In specificembodiments, a compound of Formula (I) or a form thereof, or amedicament thereof is administered to a subject that will or may benefitfrom enhanced Smn protein expression.

In certain embodiments, a compound of Formula (I) or a form thereof, ora medicament thereof is administered to a human that has an age in arange of from about 0 months to about 6 months old, from about 6 toabout 12 months old, from about 6 to about 18 months old, from about 18to about 36 months old, from about 1 to about 5 years old, from about 5to about 10 years old, from about 10 to about 15 years old, from about15 to about 20 years old, from about 20 to about 25 years old, fromabout 25 to about 30 years old, from about 30 to about 35 years old,from about 35 to about 40 years old, from about 40 to about 45 yearsold, from about 45 to about 50 years old, from about 50 to about 55years old, from about 55 to about 60 years old, from about 60 to about65 years old, from about 65 to about 70 years old, from about 70 toabout 75 years old, from about 75 to about 80 years old, from about 80to about 85 years old, from about 85 to about 90 years old, from about90 to about 95 years old or from about 95 to about 100 years old.

In some embodiments, a compound of Formula (I) or a form thereof, or amedicament thereof is administered to a human infant. In otherembodiments, a compound of Formula (I) or a form thereof, or amedicament thereof is administered to a human toddler. In otherembodiments, a compound of Formula (I) or a form thereof, or amedicament thereof is administered to a human child. In otherembodiments, a compound of Formula (I) or a form thereof, or amedicament thereof is administered to a human adult. In yet otherembodiments, a compound of Formula (I) or a form thereof, or amedicament thereof is administered to an elderly human.

In some embodiments, a compound of Formula (I) or a form thereof, or amedicament thereof is administered to a patient to prevent the onset ofSMA in a patient at risk of developing SMA. In other embodiments, aneffective amount of a compound of Formula (I) or a form thereof, or amedicament thereof, is administered to a patient to prevent the onset ofSMA in a patient at risk of developing SMA. In other embodiments, aprophylactically effective amount of a compound of Formula (I) or a formthereof, or a medicament thereof, is administered to a patient toprevent the onset of SMA in a patient at risk of developing SMA. Inother embodiments, a therapeutically effective amount of a compound ofFormula (I) or a form thereof, or a medicament thereof, is administeredto a patient to prevent the onset of SMA in a patient at risk ofdeveloping SMA.

In some embodiments, a compound of Formula (I) or a form thereof, or amedicament thereof, is administered to an SMA patient to treat orameliorate SMA. In other embodiments, an effective amount of a compoundof Formula (I) or a form thereof, or a medicament thereof, isadministered to an SMA patient to treat or ameliorate SMA. In otherembodiments, a prophylactically effective amount of a compound ofFormula (I) or a form thereof, or a medicament thereof, is administeredto an SMA patient to prevent advancement of SMA. In other embodiments, atherapeutically effective amount of a compound of Formula (I) or a formthereof, or a medicament thereof, is administered to an SMA patient totreat or ameliorate SMA.

Mode of Administration

When administered to a patient, a compound of Formula (I) or a formthereof is preferably administered as a component of a composition thatoptionally comprises a pharmaceutically acceptable carrier, excipient ordiluent. The composition can be administered orally, or by any otherconvenient route, for example, by infusion or bolus injection, byabsorption through epithelial or mucocutaneous linings (e.g., oralmucosa, rectal, and intestinal mucosa) and may be administered togetherwith another biologically active agent. Administration can be systemicor local. Various delivery systems are known, e.g., encapsulation inliposomes, microparticles, microcapsules, capsules, and can be used toadminister the compound.

Methods of administration include but are not limited to parenteral,intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous,intranasal, epidural, oral, sublingual, intranasal, intracerebral,intravaginal, transdermal, rectally, by inhalation, or topically,particularly to the ears, nose, eyes, or skin. The mode ofadministration is left to the discretion of the practitioner. In mostinstances, administration will result in the release of a compound intothe bloodstream. In a specific embodiment, a compound is administeredorally.

Dosage and Dosage Forms

The amount of a compound of Formula (I) or a form thereof that will beeffective in the treatment of SMA depend, e.g., on the route ofadministration, the type of SMA, the general health of the subject,ethnicity, age, weight, and gender of the subject, diet, time, and theseverity of SMA, and should be decided according to the judgment of thepractitioner and each patient's or subject's circumstances.

In specific embodiments, an “effective amount,” “prophylacticallyeffective amount” or “therapeutically effective amount” in the contextof the administration of a compound of Formula (I) or a form thereof, orcomposition or medicament thereof refers to an amount of a compound ofFormula (I) which has a therapeutic effect and/or beneficial effect. Incertain specific embodiments, an “effective amount,” “prophylacticallyeffective amount” or “therapeutically effective amount” in the contextof the administration of a compound of Formula (I) or a form thereof, orcomposition or medicament thereof results in one, two or more of thefollowing effects: (i) reduces or ameliorates the severity of SMA; (ii)delays onset of SMA; (iii) inhibits the progression of SMA; (iv) reduceshospitalization of a subject; (v) reduces hospitalization length for asubject; (vi) increases the survival of a subject; (vii) improves thequality of life of a subject; (viii) reduces the number of symptomsassociated with SMA; (ix) reduces or ameliorates the severity of asymptom(s) associated with SMA; (x) reduces the duration of a symptomassociated with SMA; (xi) prevents the recurrence of a symptomassociated with SMA; (xii) inhibits the development or onset of asymptom of SMA; and/or (xiii) inhibits of the progression of a symptomassociated with SMA. In certain embodiments, an effective amount of acompound of Formula (I) or a form thereof is an amount effective toenhance inclusion of exon 7 of SMN2 into SMN2 mRNA that is transcribedfrom the SMN2 gene and increases the levels of Smn protein produced fromthe SMN2 gene and thus producing a desired beneficial effect in asubject in need thereof. In some instances, the desired effect can bedetermined by analyzing or quantifying: (1) the inclusion of exon 7 ofSMN2 into mRNA that is transcribed from the SMN2 gene; or (2) the levelsof Smn protein produced from the SMN2 gene. Non-limiting examples ofeffective amounts of a compound of Formula (I) or a form thereof aredescribed herein.

For example, the effective amount may be the amount required to treatSMA in a human subject in need thereof, or the amount required toenhance inclusion of exon 7 of SMN2 into mRNA that is transcribed fromthe SMN2 gene in a human subject in need thereof, or the amount requiredto increase levels of Smn protein produced from the SMN2 gene in a humansubject in need thereof. In a specific embodiment, the human subject isan SMA patient.

In general, the effective amount will be in a range of from about 0.001mg/kg/day to about 500 mg/kg/day for a patient or subject having aweight in a range of between about 1 kg to about 200 kg. The typicaladult subject is expected to have a median weight in a range of betweenabout 70 and about 100 kg.

Within the scope of the present description, the “effective amount” of acompound of Formula (I) or a form thereof for use in the manufacture ofa medicament, the preparation of a pharmaceutical kit or in a method fortreating SMA in a human subject in need thereof, is intended to includean amount in a range of from about 0.001 mg to about 35,000 mg. In aspecific embodiment, the human subject is an SMA patient.

The compositions described herein are formulated for administration tothe subject via any drug delivery route known in the art. Nonlimitingexamples include oral, ocular, rectal, buccal, topical, nasal,ophthalmic, subcutaneous, intramuscular, intravenous (bolus andinfusion), intracerebral, transdermal, and pulmonary routes ofadministration.

Pharmaceutical Compositions

Embodiments described herein include the use of a compound of Formula(I) or a form thereof in a pharmaceutical composition. In a specificembodiment, described herein is the use of a compound of Formula (I) ora form thereof in a pharmaceutical composition for treating SMA in ahuman subject in need thereof comprising administering an effectiveamount of a compound of Formula (I) or a form thereof in admixture witha pharmaceutically acceptable excipient. In a specific embodiment, thehuman subject is an SMA patient.

A compound of Formula (I) or a form thereof may optionally be in theform of a composition comprising the compound or a form thereof and anoptional carrier, excipient or diluent. Other embodiments providedherein include pharmaceutical compositions comprising an effectiveamount of a compound of Formula (I) or a form thereof and apharmaceutically acceptable carrier, excipient, or diluent. In aspecific embodiment, the pharmaceutical compositions are suitable forveterinary and/or human administration. The pharmaceutical compositionsprovided herein can be in any form that allows for the composition to beadministered to a subject.

In a specific embodiment and in this context, the term “pharmaceuticallyacceptable carrier, excipient or diluent” means a carrier, excipient ordiluent approved by a regulatory agency of the Federal or a stategovernment or listed in the U.S. Pharmacopeia or other generallyrecognized pharmacopeia for use in animals, and more particularly inhumans. The term “carrier” refers to a diluent, adjuvant (e.g., Freund'sadjuvant (complete and incomplete)), excipient, or vehicle with which atherapeutic agent is administered. Such pharmaceutical carriers can besterile liquids, such as water and oils, including those of petroleum,animal, vegetable or synthetic origin, such as peanut oil, soybean oil,mineral oil, sesame oil and the like. Water is a specific carrier forintravenously administered pharmaceutical compositions. Saline solutionsand aqueous dextrose and glycerol solutions can also be employed asliquid carriers, particularly for injectable solutions.

Typical compositions and dosage forms comprise one or more excipients.Suitable excipients are well-known to those skilled in the art ofpharmacy, and non limiting examples of suitable excipients includestarch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk,silica gel, sodium stearate, glycerol monostearate, talc, sodiumchloride, dried skim milk, glycerol, propylene, glycol, water, ethanoland the like. Whether a particular excipient is suitable forincorporation into a pharmaceutical composition or dosage form dependson a variety of factors well known in the art including, but not limitedto, the way in which the dosage form will be administered to a patientand the specific active ingredients in the dosage form. Further providedherein are anhydrous pharmaceutical compositions and dosage formscomprising one or more compounds of Formula (I) or a form thereof asdescribed herein. The compositions and single unit dosage forms can takethe form of solutions or syrups (optionally with a flavoring agent),suspensions (optionally with a flavoring agent), emulsions, tablets(e.g., chewable tablets), pills, capsules, granules, powder (optionallyfor reconstitution), taste-masked or sustained-release formulations andthe like.

Pharmaceutical compositions provided herein that are suitable for oraladministration can be presented as discrete dosage forms, such as, butare not limited to, tablets, caplets, capsules, granules, powder, andliquids. Such dosage forms contain predetermined amounts of activeingredients, and may be prepared by methods of pharmacy well known tothose skilled in the art.

Examples of excipients that can be used in oral dosage forms providedherein include, but are not limited to, binders, fillers, disintegrants,and lubricants.

Biomarkers

In certain embodiments, the amount of mRNA that is transcribed from theSMN1 gene and/or SMN2 gene and includes exon 7 of SMN1 and/or SMN2 isused as a biomarker for SMA. In certain embodiments, the amount of mRNAthat is transcribed from the SMN1 gene and/or SMN2 gene and does notinclude exon 7 of SMN1 and/or SMN2 is used as a biomarker for SMA. Inother embodiments, the amount of mRNA that is transcribed from the SMN1and/or SMN2 gene and includes exon 7 of SMN1 and/or SMN2 is used as abiomarker for an SMA patient being treated with a compound, such asdisclosed herein. In other embodiments, the amount of mRNA that istranscribed from the SMN1 and/or SMN2 gene and does not include exon 7of SMN1 and/or SMN2 is used as a biomarker for an SMA patient beingtreated with a compound, such as disclosed herein. In some embodiments,a change in the amount of mRNA that is transcribed from the SMN1 and/orSMN2 gene and includes exon 7 of SMN1 and/or SMN2 and a correspondingchange in the amount of mRNA that is transcribed from the SMN1 and/orSMN2 gene and does not include exon 7 of SMN1 and/or SMN2 is a biomarkerfor a patient being treated with a compound, such as disclosed herein.In a specific embodiment, the patient is an SMA patient.

In a specific embodiment, an increase in the amount of mRNA that istranscribed from the SMN1 and/or SMN2 gene and includes exon 7 of SMN1and/or SMN2 and a corresponding decrease in the amount of mRNA that istranscribed from the SMN1 and/or SMN2 gene and does not include exon 7of SMN1 and/or SMN2 after the administration of a compound (e.g., acompound of Formula (I) disclosed herein) indicates that the compoundmay be effective to treat SMA. In another specific embodiment, adecrease in the amount of mRNA that is transcribed from the SMN2 geneand includes exon 7 of SMN2 and a corresponding increase in the amountof mRNA that is transcribed from the SMN2 gene and does not include exon7 of SMN2 after the administration of a compound (e.g., a compound ofFormula (I) disclosed herein) indicates that the compound will not beeffective to treat SMA. In accordance with these embodiments, an SMNprimer(s) and/or an SMN probe described below can be used in assays,such as PCR (e.g., qPCR) and RT-PCR (e.g., RT-qPCR or endpoint RT-PCR)to assess and/or quantify the amount of mRNA that is transcribed fromthe SMN1 gene and/or SMN2 gene and does or does not include exon 7 ofSMN1 and/or SMN2.

In one embodiment, provided herein are SMN primers and/or SMN probes(e.g., a forward primer having the nucleotide sequence of SEQ ID NO. 1,7, 8, 11 or 13; and/or a reverse primer having the nucleotide sequenceof SEQ ID NO. 9 or 12; and/or an SMN probe such as a SEQ ID NO. 3 or 10)for amplifying nucleic acids encoding or encoded by human SMN1 and/orSMN2. These primers can be used as primers in, e.g., RT-PCR (such asRT-PCR, endpoint RT-PCR and/or RT-qPCR as described herein or as knownto one skilled in the art), PCR (such as qPCR) or rolling circleamplification, and as probes in hybridization assays, such as a Northernblot and/or a Southern blot assay. As utilized in the BiologicalExamples herein, endpoint RT-PCR is a reverse transcription-polymerasechain reaction that is carried out for a certain number of amplificationcycles (or until starting materials are exhausted) following by aquantification of each of the DNA products using, e.g., gelelectrophoretic separation, staining with a fluorescent dye,quantification of fluorescence and the like.

SEQ ID NO. 1 hybridizes to DNA or RNA comprising nucleotidescorresponding to nucleotides 22 to 40 of exon 7 of SMN1 and/or SMN2, SEQID NO. 2 hybridizes to DNA or RNA comprising nucleotides correspondingto nucleotides 4 to 26 of the firefly luciferase coding sequence; SEQ IDNO. 7 hydridizes to nucleic acid sequences (e.g., the sense strand ofDNA) comprising nucleotides corresponding to nucleotides 32 to 54 ofexon 7 of SMN1 and/or SMN2 and nucleotides 1 to 4 of exon 8 of SMN1and/or SMN2, SEQ ID NO. 8 hybridizes to nucleic acid sequences (e.g.,the sense strand of DNA) comprising nucleotides corresponding, in order,to nucleotides 87 to 111 of exon 7 of SMN1 and/or SMN2 and nucleotides 1to 3 of exon 8 of SMN1 and/or SMN2, SEQ ID NO. 9 hybridizes to nucleicacid sequences (e.g., the antisense strand of DNA or RNA) comprisingnucleotides corresponding to nucleotides 39 to 62 of exon 8 of SMN1and/or SMN2, SEQ ID NO. 11 hybridizes to nucleic acid sequences (e.g.,the sense strand of DNA) comprising nucleotides corresponding tonucleotides 43 to 63 of exon 6 of SMN1 and/or SMN2, SEQ ID NO. 12hybridizes to nucleic acid sequences (e.g., the antisense strand of DNAor RNA) comprising nucleotides corresponding to nucleotides 51 to 73 ofexon 8 of SMN1 and/or SMN2, and SEQ ID NO. 13 hybridizes to nucleic acidsequence (e.g., the sense strand of DNA) comprising nucleotidescorresponding to nucleotides 22 to 46 of exon 6 of SMN1 and/or SMN2.

Accordingly, an oligonucleotide corresponding to SEQ ID NO. 9, 11, 12and/or 13 can be used in an amplification reaction to amplify nucleicacids encoding or encoded by human SMN1 and/or SMN2 lacking exon 7 ofhuman SMN1 and/or SMN2 and nucleic acid encoding or encoded by humanSMN1 and/or SMN2 and includes exon 7 of human SMN1 and/or SMN2. Incontrast, an oligonucleotide corresponding to SEQ ID NO. 8 inconjunction with a downstream reverse primer (e.g., SEQ ID NO. 9 or 12)can be used to amplify nucleic acids encoding or encoded by human SMN1and/or SMN2 lacking exon 7 of human SMN1 and/or SMN2 and anoligonucleotide corresponding to SEQ ID NO. 1 and 7 in conjunction witha downstream reverse primer (e.g., SEQ ID NO. 9 or 12) can be used toamplify nucleic acids encoding or encoded by human SMN1 and/or humanSMN2 and includes exon 7 of SMN1 and/or SMN2.

SEQ ID NO. 3 hybridizes to nucleic acid sequences (e.g., the sensestrand of DNA) comprising nucleotides corresponding, in order, tonucleotides 50 to 54 of exon 7 of human SMN1 and/or SMN2 and nucleotides1 to 21 of exon 8 of human SMN1 and/or SMN2, and SEQ ID NO. 10hybridizes to nucleic acid sequences (e.g., the sense strand of DNA)comprising nucleotides corresponding to nucleotides 7 to 36 of exon 8 ofhuman SMN1 and/or SMN2. SEQ ID NO. 3 is useful as a probe to detect mRNAthat is transcribed from the minigene and includes exon 7 of SMN1 and/orSMN2, described herein or described in International Publication No. WO2009/151546 or U.S. Patent Application Publication No. 2011/0086833(each of which is incorporated herein by reference in its entirety) andto detect mRNA that is transcribed from human SMN1 and/or SMN2 andincludes exon 7 of SMN1 and/or SMN2. In addition, SEQ ID NO. 10 isuseful as a probe to detect mRNA that is transcribed from the minigeneand does or does not include exon 7 of SMN1 and/or SMN2 and to detectmRNA that is transcribed from human SMN1 and/or SMN2, described hereinor as described in International Publication No. WO 2009/151546 or U.S.Patent Application Publication No. 2011/0086833, each of which isincorporated herein by reference in its entirety.

In a specific embodiment, a primer and/or probe described below in theBiological Examples (e.g., SMN primers such as SEQ ID NO. 1, 7, 11 or 13and/or SEQ ID NO. 2, 9 or 12, and/or SMN probes such as a SEQ ID NO. 3or 10) is used in an assay, such as RT-PCR, RT-qPCR, endpoint RT-PCR,PCR, qPCR, rolling circle amplification and, as applicable, Northernblot or Southern blot (e.g., an assay such as described below in theBiological Examples), to determine whether a compound (e.g., a compoundof Formula (I) or a form thereof) enhances the inclusion of exon 7 ofSMN1 and/or SMN2 into mRNA that is transcribed from an SMN1 and/or SMN2gene.

In another embodiment, a primer and/or probe described below in theBiological Examples (e.g., SMN primers such as SEQ ID NO. 1, 7, 11 or 13and/or SEQ ID NO. 9 or 12, and/or SMN probes such as a SEQ ID NO. 3 or10) is used in an assay, such as RT-PCR, RT-qPCR, endpoint RT-PCR, PCR,qPCR, rolling circle amplification and, as applicable, Northern blot orSouthern blot (e.g., an assay such as described below in the BiologicalExamples), to monitor the amount of mRNA that is transcribed from theSMN1 and/or SMN2 gene and includes exon 7 of SMN1 and/or SMN2 in apatient sample. In a specific embodiment, the patient is an SMA patient.

In another embodiment, a primer and/or probe described below in theBiological Examples (e.g., SMN primers such as SEQ ID NO. 1, 7, 11 or 13and/or SEQ ID NO. 9 or 12, and/or SMN probes such as a SEQ ID NO. 3 or10) is used in an assay, such as RT-PCR, RT-qPCR, endpoint RT-PCR, PCR,qPCR, rolling circle amplification and, as applicable, Northern blot orSouthern blot (e.g., an assay such as described below in the BiologicalExamples), to monitor a patient's response to a compound (e.g., acompound of Formula (I) or a form thereof). In a specific embodiment,the patient is an SMA patient.

A sample (e.g., a blood sample, PBMC sample, or tissue sample, such as askin or muscle tissue sample) from a patient can be obtained usingtechniques known to one skilled in the art and the primers and/or probesdescribed in the Biological Examples below can be used in assays (e.g.,PCR, RT-PCR, RT-qPCR, qPCR, endpoint RT-PCR, rolling circleamplification, Northern blot and Southern blot) to determine the amountof mRNA that is transcribed from the SMN1 and/or SMN2 genes (e.g., theamount of mRNA that includes exon 7 of SMN2 transcribed from the SMN2gene). A sample derived from a patient refers to a sample that isprocessed and/or manipulated after being obtained from the patient usingtechniques known to one skilled in the art. For example, a sample from apatient can be processed to, e.g., extract RNA, using techniques knownto one of skill in the art. A sample from a patient can be processed to,e.g., extract RNA and the RNA is reversed transcribed to produce cDNA.In a specific embodiment, the patient is an SMA patient.

In a specific embodiment, provided herein is a method for detecting theamount of mRNA that is transcribed from the SMN1 and/or SMN2 gene andincludes exon 7 of SMN1 and/or SMN2, comprising: (a) contacting apatient sample (e.g., blood sample or tissue sample) or a sample derivedfrom a patient (e.g., a blood sample or tissue sample that has beenprocessed to extract RNA) with a forward SMN primer described below(e.g., SEQ ID NO. 1, 7, 11 or 13) and/or a reverse SMN primer describedherein (e.g., SEQ ID NO. 9 or 12) along with applicable components for,e.g., an RT-PCR (e.g., endpoint RT-PCR and/or RT-qPCR), PCR (e.g., qPCR)or rolling circle amplification; and (b) detecting the amount of mRNAthat is transcribed from the SMN1 and/or SMN2 gene and includes exon 7of SMN1 and/or SMN2. In certain embodiments, the sample is from orderived from a patient administered a compound, such as a compound ofFormula (I) or a form thereof as described herein. In a specificembodiment, the patient is an SMA patient.

In another specific embodiment, provided herein is a method fordetecting the amount of mRNA that is transcribed from the SMN1 and SMN2genes, comprising: (a) contacting a patient sample (e.g., blood sampleor tissue sample) or a sample derived from a patient (e.g., a bloodsample or tissue sample that has been processed to extract RNA) with aforward SMN primer described below (e.g., SEQ ID NO. 1, 7, 11 or 13)and/or a reverse SMN primer described herein (e.g., SEQ ID NO. 9 or 12)along with applicable components for, e.g., an RT-PCR (e.g., endpointRT-PCR and/or RT-qPCR), PCR (e.g., qPCR) or rolling circleamplification; and (b) detecting the amount of mRNA that is transcribedfrom the SMN1 and SMN2 genes. In certain embodiments, the sample is fromor derived from a patient administered a compound, such as a compound ofFormula (I) or a form thereof as described herein. In a specificembodiment, the patient is an SMA patient.

The amount of mRNA that is transcribed from the human SMN1 and SMN2genes that includes exon 7 of SMN1 and SMN2 and the amount of mRNA thatis transcribed from the human SMN1 and SMN2 genes and does not includeexon 7 of SMN1 and SMN2 can be differentiated from each other by, e.g.,size of the RNA or DNA fragment generated from SMN1 and SMN2 mRNA thatincludes exon 7 of SMN1 and SMN2 and from SMN1 and SMN2 mRNA that do notinclude exon 7 of SMN1 and SMN2.

In another specific embodiment, provided herein is a method fordetecting the amount of mRNA that is transcribed from the SMN1 and/orSMN2 gene and does not include exon 7 of SMN1 and/or SMN2, comprising:(a) contacting a patient sample (e.g., blood sample or tissue sample) ora sample derived from a patient (e.g., a blood sample or tissue samplethat has been processed to extract RNA) with a forward SMN primerdescribed below (e.g., SEQ ID NO. 8, 11 or 13) and/or a reverse SMNprimer described herein (e.g., SEQ ID NO. 9 or 12) along with applicablecomponents for, e.g., an RT-PCR (e.g., endpoint RT-PCR and/or RT-qPCR),PCR (e.g., qPCR) or rolling circle amplification; and (b) detecting theamount of mRNA that is transcribed from the SMN1 and/or SMN2 gene anddoes not include exon 7 of SMN1 and/or SMN2. In certain embodiments, thesample is from or derived from a patient administered a compound, suchas a compound of Formula (I) or a form thereof as described herein. In aspecific embodiment, the patient is an SMA patient.

In another specific embodiment, provided herein is a method fordetecting the amount of mRNA that is transcribed from the SMN1 and/orSMN2 gene and includes exon 7 of SMN1 and/or SMN2, comprising: (a)contacting a patient sample (e.g., blood sample or tissue sample) or asample derived from a patient (e.g., a blood sample or tissue samplethat has been processed to extract RNA) with an SMN probe describedbelow (e.g., SEQ ID NO. 3 or 10) along with applicable components, e.g.,of an RT-PCR (e.g., endpoint RT-PCR and/or RT-qPCR), PCR (e.g., qPCR),rolling circle amplification and, as applicable, Northern blot orSouthern blot; and (b) detecting the amount of mRNA that is transcribedfrom the SMN1 and/or SMN2 gene and includes exon 7 of SMN1 and/or SMN2.In certain embodiments, the sample is from or derived from a patientadministered a compound, such as a compound of Formula (I) or a formthereof as described herein. In a specific embodiment, the patient is anSMA patient.

In another specific embodiment, provided herein is a method fordetecting the amount of mRNA that is transcribed from the SMN1 and SMN2genes, comprising: (a) contacting a patient sample (e.g., blood sampleor tissue sample) or a sample derived from a patient (e.g., a bloodsample or tissue sample that has been processed to extract RNA) with anSMN probe described below (e.g., SEQ ID NO. 3 or 10) along withapplicable components for, e.g., an RT-PCR (e.g., endpoint RT-PCR and/orRT-qPCR), PCR (e.g., qPCR), rolling circle amplification and, asapplicable, Northern blot or Southern blot; and (b) detecting the amountof mRNA that is transcribed from the SMN1 and SMN2 genes.

The amount of mRNA that is transcribed from the human SMN1 and SMN2genes that includes exon 7 of SMN1 and SMN2 and the amount of mRNA thatis transcribed from the human SMN1 and SMN2 genes and does not includeexon 7 of SMN1 and SMN2 can be differentiated from each other by, e.g.,size of the RNA or DNA fragment generated from SMN1 and SMN2 mRNA thatincludes exon 7 of SMN1 and SMN2 and from SMN1 and SMN2 mRNA that do notinclude exon 7 of SMN1 and SMN2. In certain embodiments, the sample isfrom or derived from a patient administered a compound, such as acompound of Formula (I) or a form thereof as described herein. In aspecific embodiment, the patient is an SMA patient.

In another specific embodiment, provided herein is a method fordetecting the amount of mRNA that is transcribed from the SMN1 and/orSMN2 gene and does not include exon 7 of SMN1 and/or SMN2, comprising:(a) contacting a patient sample (e.g., blood sample or tissue sample) ora sample derived from a patient (e.g., a blood sample or tissue samplethat has been processed to extract RNA) with an SMN probe describedbelow (e.g., SEQ ID NO. 10) along with applicable components for, e.g.,an RT-PCR (e.g., endpoint RT-PCR and/or RT-qPCR), PCR (e.g., qPCR),rolling circle amplification, or Northern blot or Southern blot; and (b)detecting the amount of mRNA that is transcribed from the SMN1 and/orSMN2 gene and does not include exon 7 of SMN1 and/or SMN2. In certainembodiments, the sample is from or derived from a patient administered acompound, such as a compound of Formula (I) or a form thereof asdescribed herein. In a specific embodiment, the patient is an SMApatient.

In a specific embodiment, provided herein is a method for detecting theamount of mRNA that is transcribed from the SMN1 and/or SMN2 gene andincludes exon 7 of SMN1 and/or SMN2, comprising: (a) contacting apatient sample (e.g., blood sample or tissue sample) or a sample derivedfrom a patient (e.g., a blood sample or tissue sample that has beenprocessed to extract RNA) with a forward SMN primer described below(e.g., SEQ ID NO. 1, 7, 11 or 13) and/or a reverse SMN primer describedherein (e.g., SEQ ID NO. 9 or 12) and/or an SMN probe described herein(e.g., SEQ ID NO. 3 or 10) along with applicable components for e.g., anRT-PCR (e.g., endpoint RT-PCR and/or RT-qPCR), PCR (e.g., qPCR) orrolling circle amplification; and (b) detecting the amount of mRNA thatis transcribed from the SMN1 and/or SMN2 gene and includes exon 7 ofSMN1 and/or SMN2. In certain embodiments, the sample is from or derivedfrom a patient administered a compound, such as a compound of Formula(I) or a form thereof as described herein. In a specific embodiment, thepatient is an SMA patient.

In a specific embodiment, provided herein is a method for detecting theamount of mRNA that is transcribed from the SMN1 and SMN2 genes,comprising: (a) contacting a patient sample (e.g., blood sample ortissue sample) or a sample derived from a patient (e.g., a blood sampleor tissue sample that has been processed to extract RNA) with a forwardSMN primer described below (e.g., SEQ ID NO. 1, 7, 8, 11 or 13) and/or areverse SMN primer described herein (e.g., SEQ ID NO. 9 or 12) and/or anSMN probe described herein (e.g., SEQ ID NO. 3 or 10) along withapplicable components for e.g., an RT-PCR (e.g., endpoint RT-PCR and/orRT-qPCR), PCR (e.g., qPCR) or rolling circle amplification, asapplicable; and (b) detecting the amount of mRNA that is transcribedfrom the SMN1 and SMN2 genes. In a specific embodiment, the patient isan SMA patient.

The amount of mRNA that is transcribed from the human SMN1 and SMN2genes that includes exon 7 of SMN1 and SMN2 and the amount of mRNA thatis transcribed from the human SMN1 and SMN2 genes that do not includeexon 7 of SMN1 and SMN2 can be differentiated from each other by, e.g.,size of the RNA or DNA fragment generated from SMN1 and SMN2 mRNA thatincludes exon 7 of SMN1 and SMN2 and from SMN1 and SMN2 mRNA that doesnot include exon 7 of SMN1 and SMN2. In certain embodiments, the sampleis from or derived from a patient administered a compound, such as acompound of Formula (I) or a form thereof as described herein. In aspecific embodiment, the patient is an SMA patient.

In a specific embodiment, provided herein is a method for detecting theamount of mRNA that is transcribed from the SMN1 and/or SMN2 gene anddoes not include exon 7 of SMN1 and/or SMN2, comprising: (a) contactinga patient sample (e.g., blood sample or tissue sample) or a samplederived from a patient (e.g., a blood sample or tissue sample that hasbeen processed to extract RNA) with a forward SMN primer described below(e.g., SEQ ID NO. 8) and/or a reverse SMN primer described herein (e.g.,SEQ ID NO. 9 or 12) and/or an SMN probe described herein (e.g., SEQ IDNO. 10) along with applicable components for e.g., an RT-PCR (e.g.,endpoint RT-PCR and/or RT-qPCR), PCR (e.g., qPCR) or rolling circleamplification; and (b) detecting the amount of mRNA that is transcribedfrom the SMN1 and/or SMN2 gene and does not include exon 7 of SMN1and/or SMN2. In certain embodiments, the sample is from or derived froma patient administered a compound, such as a compound of Formula (I) ora form thereof as described herein. In a specific embodiment, thepatient is an SMA patient.

In a specific embodiment, provided herein is a method for assessing anSMA patient's response to a compound, comprising: (a) contacting an SMApatient sample (e.g., blood sample or tissue sample) or a sample derivedfrom an SMA patient (e.g., a blood sample or tissue sample that has beenprocessed to extract RNA) with a forward SMN primer described below(e.g., SEQ ID NO. 1, 7, 11 or 13) and/or a reverse SMN primer describedherein (e.g., SEQ ID NO. 9 or 12) along with applicable components fore.g., RT-PCR (e.g., endpoint RT-PCR and/or RT-qPCR), PCR (e.g., qPCR) orrolling circle amplification, wherein the sample is from or derived froman SMA patient administered a compound (e.g., a compound describedherein); and (b) detecting the amount of mRNA that is transcribed fromthe SMN1 and/or SMN2 gene and includes exon 7 of SMN1 and/or SMN2,wherein (1) an increase in the amount of mRNA that is transcribed fromthe SMN1 and/or SMN2 gene and includes exon 7 of SMN1 and/or SMN2 in thepatient sample relative to the amount of mRNA that is transcribed fromthe SMN1 and/or SMN2 gene and includes exon 7 of SMN1 and/or SMN2 in ananalogous sample (e.g., from the same type of tissue sample) from thepatient prior to administration of the compound indicates that thepatient is responsive to the compound and that the compound may be or isbeneficial and/or of therapeutic value to the patient; and (2) no changeor no substantial change in the amount of mRNA that is transcribed fromthe SMN1 and/or SMN2 gene and includes exon 7 of SMN1 and/or SMN2 in thepatient sample relative to the amount of mRNA that is transcribed fromthe SMN1 and/or SMN2 gene and includes exon 7 of SMN1 and/or SMN2 in ananalogous sample (e.g., the same type of tissue sample) from the patientprior to administration of the compound indicates that the patient isnot responsive to the compound and that the compound is not beneficialand/or of therapeutic value to the patient. In certain embodiments, thepatient's response is assessed 1 hour, 2 hours, 4 hours, 8 hours, 12hours, 16 hours, 20 hours, 1 day, 2 days, 3 days, 5 days, 7 days, 14days, 28 days, 1 month, 2 months, 3 months, 6 months, 9 months, 12months or more after administration of a compound, such as a compound ofFormula (I) or a form thereof as described herein.

In another specific embodiment, provided herein is a method forassessing an SMA patient's response to a compound, comprising: (a)administering a compound to an SMA patient; (b) contacting a sample(e.g., blood sample or tissue sample) obtained or derived from thepatient with a forward SMN primer described below (e.g., SEQ ID NO. 1,7, 11 or 13) and/or a reverse SMN primer described herein (e.g., SEQ IDNO. 9 or 12) along with applicable components for e.g., RT-PCR (e.g.,endpoint RT-PCR and/or RT-qPCR), PCR (e.g., qPCR) or rolling circleamplification; and (c) detecting the amount of mRNA that is transcribedfrom the SMN1 and/or SMN2 gene and includes exon 7 of SMN2, wherein (1)an increase in the amount of mRNA that is transcribed from the SMN1and/or SMN2 gene and includes exon 7 of SMN1 and/or SMN2 in the patientsample relative to the amount of mRNA that is transcribed from the SMN1and/or SMN2 gene and includes exon 7 of SMN1 and/or SMN2 in an analogoussample (e.g., from the same type of tissue sample) from the patientprior to administration of the compound indicates that the patient isresponsive to the compound and that the compound may be or is beneficialand/or of therapeutic value to the patient; and (2) no change or nosubstantial change in the amount of mRNA that is transcribed from theSMN1 and/or SMN2 gene and includes exon 7 of SMN1 and/or SMN2 in thepatient sample relative to the amount of mRNA that is transcribed fromthe SMN1 and/or SMN2 gene and includes exon 7 of SMN1 and/or SMN2 in ananalogous sample (e.g., from the same type of tissue sample) from thepatient prior to administration of the compound indicates that thepatient is not responsive to the compound and that the compound is notbeneficial and/or of therapeutic value to the patient. In certainembodiments, the patient's response is assessed 1 hour, 2 hours, 4hours, 8 hours, 12 hours, 16 hours, 20 hours, 1 day, 2 days, 3 days, 5days, 7 days, 14 days, 28 days, 1 month, 2 months, 3 months, 6 months, 9months, 12 months or more after administration of a compound, such as acompound of Formula (I) or a form thereof as described herein.

In a specific embodiment, provided herein is a method for assessing anSMA patient's response to a compound, comprising: (a) contacting an SMApatient sample (e.g., blood sample or tissue sample) or a sample derivedfrom an SMA patient (e.g., a blood sample or tissue sample that has beenprocessed to extract RNA) with a forward SMN primer described below(e.g., SEQ ID NO. 1, 7, 11 or 13) and/or a reverse SMN primer describedherein (e.g., SEQ ID NO. 9 or 12) and/or an SMN probe (e.g., SEQ ID NO.3 or 10) along with applicable components for e.g., RT-PCR (e.g.,endpoint RT-PCR and/or RT-qPCR), PCR (e.g., qPCR) or rolling circleamplification, wherein the sample is from or derived from an SMA patientadministered a compound (e.g., a compound of Formula (I) or a formthereof as described herein); and (b) detecting the amount of mRNA thatis transcribed from the SMN1 and/or SMN2 gene and includes exon 7 ofSMN1 and/or SMN2, wherein (1) an increase in the amount of mRNA that istranscribed from the SMN1 and/or SMN2 gene and includes exon 7 of SMN1and/or SMN2 in the patient sample relative to the amount of mRNA that istranscribed from the SMN1 and/or SMN2 gene and includes exon 7 of SMN1and/or SMN2 in an analogous sample (e.g., from the same type of tissuesample) from the patient prior to administration of the compoundindicates that the patient is responsive to the compound and that thecompound may be or is beneficial and/or of therapeutic value to thepatient; and (2) no change or no substantial change in the amount ofmRNA that is transcribed from the SMN1 and/or SMN2 gene and includesexon 7 of SMN1 and/or SMN2 in the patient sample relative to the amountof mRNA that is transcribed from the SMN1 and/or SMN2 gene and includesexon 7 of SMN1 and/or SMN2 in an analogous sample (e.g., from the sametype of tissue sample) from the patient prior to administration of thecompound indicates that the patient is not responsive to the compoundand that the compound is not beneficial and/or of therapeutic value tothe patient. In certain embodiments, the patient's response is assessed1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 16 hours, 20 hours, 1 day,2 days, 3 days, 5 days, 7 days, 14 days, 28 days, 1 month, 2 months, 3months, 6 months, 9 months, 12 months or more after administration of acompound, such as a compound of Formula (I) or a form thereof asdescribed herein.

In another specific embodiment, provided herein is a method forassessing an SMA patient's response to a compound, comprising: (a)administering a compound to an SMA patient; (b) contacting a sample(e.g., blood sample or tissue sample) obtained or derived from thepatient with a forward SMN primer described below (e.g., SEQ ID NO. 1,7, 11 or 13) and/or a reverse SMN primer described herein (e.g., SEQ IDNO. 9 or 12) and/or an SMN probe (e.g., SEQ ID NO. 3 or 10) along withapplicable components for e.g., RT-PCR (e.g., endpoint RT-PCR and/orRT-qPCR), PCR (e.g., qPCR) or rolling circle amplification; and (c)detecting the amount of mRNA that is transcribed from the SMN1 and/orSMN2 gene and includes exon 7 of SMN1 and/or SMN2, wherein (1) anincrease in the amount of mRNA that is transcribed from the SMN1 and/orSMN2 gene and includes exon 7 of SMN1 and/or SMN2 in the patient samplerelative to the amount of mRNA that is transcribed from the SMN1 and/orSMN2 gene and includes exon 7 of SMN1 and/or SMN2 in an analogous sample(e.g., from the same type of tissue sample) from the patient prior toadministration of the compound indicates that the patient is responsiveto the compound and that the compound may be or is beneficial and/or oftherapeutic value to the patient; and (2) no change or no substantialchange in the amount of mRNA that is transcribed from the SMN1 and/orSMN2 gene and includes exon 7 of SMN1 and/or SMN2 in the patient samplerelative to the amount of mRNA that is transcribed from the SMN1 and/orSMN2 gene and includes exon 7 of SMN1 and/or SMN2 in an analogous sample(e.g., from the same type of tissue sample) from the patient prior toadministration of the compound indicates that the patient is notresponsive to the compound and that the compound is not beneficialand/or of therapeutic value to the patient. In certain embodiments, thepatient's response is assessed 1 hour, 2 hours, 4 hours, 8 hours, 12hours, 16 hours, 20 hours, 1 day, 2 days, 3 days, 5 days, 7 days, 14days, 28 days, 1 month, 2 months, 3 months, 6 months, 9 months, 12months or more after administration of a compound, such as a compound ofFormula (I) or a form thereof as described herein.

In a specific embodiment, provided herein is a method for assessing anSMA patient's response to a compound, comprising: (a) contacting an SMApatient sample (e.g., blood sample or tissue sample) or a sample derivedfrom an SMA patient (e.g., a blood sample or tissue sample that has beenprocessed to extract RNA) with a forward SMN primer described below(e.g., SEQ ID NO. 8, 11 or 13) and/or a reverse SMN primer describedherein (e.g., SEQ ID NO. 9 or 12) along with applicable components fore.g., RT-PCR (e.g., endpoint RT-PCR and/or RT-qPCR), PCR (e.g., qPCR) orrolling circle amplification, wherein the sample is from or derived froman SMA patient administered a compound (e.g., a compound of Formula (I)or a form thereof as described herein); and (b) detecting the amount ofmRNA that is transcribed from the SMN1 and/or SMN2 gene and does notinclude exon 7 of SMN1 and/or SMN2, wherein (1) a decrease in the amountof mRNA that is transcribed from the SMN1 and/or SMN2 gene and does notinclude exon 7 of SMN1 and/or SMN2 in the patient sample relative to theamount of mRNA that is transcribed from the SMN1 and/or SMN2 gene anddoes not include exon 7 of SMN1 and/or SMN2 in an analogous sample(e.g., from the same type of tissue sample) from the patient prior toadministration of the compound indicates that the patient is responsiveto the compound and that the compound may be or is beneficial and/or oftherapeutic value to the patient; and (2) no change or no substantialchange in the amount of mRNA that is transcribed from the SMN1 and/orSMN2 gene and does not include exon 7 of SMN1 and/or SMN2 in the patientsample relative to the amount of mRNA that is transcribed from the SMN1and/or SMN2 gene and does not include exon 7 of SMN1 and/or SMN2 in ananalogous sample (e.g., from the same type of tissue sample) from thepatient prior to administration of the compound indicates that thepatient is not responsive to the compound and that the compound is notbeneficial and/or of therapeutic value to the patient. In certainembodiments, the patient's response is assessed 1 hour, 2 hours, 4hours, 8 hours, 12 hours, 16 hours, 20 hours, 1 day, 2 days, 3 days, 5days, 7 days, 14 days, 28 days, 1 month, 2 months, 3 months, 6 months, 9months, 12 months or more after administration of a compound, such as acompound of Formula (I) or a form thereof as described herein.

In another specific embodiment, provided herein is a method forassessing an SMA patient's response to a compound, comprising: (a)administering a compound to an SMA patient; (b) contacting a sample(e.g., blood sample or tissue sample) obtained or derived from thepatient with a forward SMN primer described below (e.g., SEQ ID NO. 8,11 or 13) and/or a reverse SMN primer described herein (e.g., SEQ ID NO.9 or 12) along with applicable components for e.g., RT-PCR (e.g.,endpoint RT-PCR and/or RT-qPCR), PCR (e.g., qPCR) or rolling circleamplification; and (c) detecting the amount of mRNA that is transcribedfrom the SMN1 and/or SMN2 gene and does not include exon 7 of SMN1and/or SMN2, wherein (1) a decrease in the amount of mRNA that istranscribed from the SMN1 and/or SMN2 gene and does not include exon 7of SMN1 and/or SMN2 in the patient sample relative to the amount of mRNAthat is transcribed from the SMN1 and/or SMN2 gene and does not includeexon 7 of SMN1 and/or SMN2 in an analogous sample (e.g., from the sametype of tissue sample) from the patient prior to administration of thecompound indicates that the patient is responsive to the compound andthat the compound may be or is beneficial and/or of therapeutic value tothe patient; and (2) no change or no substantial change in the amount ofmRNA that is transcribed from the SMN1 and/or SMN2 gene and does notinclude exon 7 of SMN1 and/or SMN2 in the patient sample relative to theamount of mRNA that is transcribed from the SMN1 and/or SMN2 gene anddoes not include exon 7 of SMN1 and/or SMN2 in an analogous sample(e.g., from the same type of tissue sample) from the patient prior toadministration of the compound indicates that the patient is notresponsive to the compound and that the compound is not beneficialand/or of therapeutic value to the patient. In certain embodiments, thepatient's response is assessed 1 hour, 2 hours, 4 hours, 8 hours, 12hours, 16 hours, 20 hours, 1 day, 2 days, 3 days, 5 days, 7 days, 14days, 28 days, 1 month, 2 months, 3 months, 6 months, 9 months, 12months or more after administration of a compound, such as a compound ofFormula (I) or a form thereof as described herein.

In a specific embodiment, provided herein is a method for assessing anSMA patient's response to a compound, comprising: (a) contacting an SMApatient sample (e.g., blood sample or tissue sample) or a sample derivedfrom an SMA patient (e.g., a blood sample or tissue sample that has beenprocessed to extract RNA) with a forward SMN primer described below(e.g., SEQ ID NO. 8, 11 or 13) and/or a reverse SMN primer describedherein (e.g., SEQ ID NO. 9 or 12) and/or an SMN probe (e.g., SEQ ID NO.10) along with applicable components for e.g., RT-PCR (e.g., endpointRT-PCR and/or RT-qPCR), PCR (e.g., qPCR) or rolling circleamplification, wherein the sample is from or derived from an SMA patientadministered a compound (e.g., a compound of Formula (I) or a formthereof as described herein); and (b) detecting the amount of mRNA thatis transcribed from the SMN1 and/or SMN2 gene and does not include exon7 of SMN1 and/or SMN2, wherein (1) a decrease in the amount of mRNA thatis transcribed from the SMN1 and/or SMN2 gene and does not include exon7 of SMN1 and/or SMN2 in the patient sample relative to the amount ofmRNA that is transcribed from the SMN1 and/or SMN2 gene and does notinclude exon 7 of SMN1 and/or SMN2 in an analogous sample (e.g., fromthe same type of tissue sample) from the patient prior to administrationof the compound indicates that the patient is responsive to the compoundand that the compound may be or is beneficial and/or of therapeuticvalue to the patient; and (2) no change or no substantial change in theamount of mRNA that is transcribed from the SMN1 and/or SMN2 gene anddoes not include exon 7 of SMN1 and/or SMN2 in the patient samplerelative to the amount of mRNA that is transcribed from the SMN1 and/orSMN2 gene and does not include exon 7 of SMN1 and/or SMN2 in ananalogous sample (e.g., from the same type of tissue sample) from thepatient prior to administration of the compound indicates that thepatient is not responsive to the compound and that the compound is notbeneficial and/or of therapeutic value to the patient. In certainembodiments, the patient's response is assessed 1 hour, 2 hours, 4hours, 8 hours, 12 hours, 16 hours, 20 hours, 1 day, 2 days, 3 days, 5days, 7 days, 14 days, 28 days, 1 month, 2 months, 3 months, 6 months, 9months, 12 months or more after administration of a compound, such as acompound of Formula (I) or a form thereof as described herein.

In another specific embodiment, provided herein is a method forassessing an SMA patient's response to a compound, comprising: (a)administering a compound to an SMA patient; (b) contacting a sample(e.g., blood sample or tissue sample) obtained or derived from thepatient with a forward SMN primer described below (e.g., SEQ ID NO. 8,11 or 13) and/or a reverse SMN primer described herein (e.g., SEQ ID NO.9 or 12) and/or an SMN probe (e.g., SEQ ID NO. 10) along with applicablecomponents for e.g., RT-PCR (e.g., endpoint RT-PCR and/or RT-qPCR), PCR(e.g., qPCR) or rolling circle amplification; and (c) detecting theamount of mRNA that is transcribed from the SMN1 and/or SMN2 gene anddoes not include exon 7 of SMN1 and/or SMN2, wherein (1) a decrease inthe amount of mRNA that is transcribed from the SMN1 and/or SMN2 geneand does not include exon 7 of SMN1 and/or SMN2 in the patient samplerelative to the amount of mRNA that is transcribed from the SMN1 and/orSMN2 gene and does not include exon 7 of SMN1 and/or SMN2 in ananalogous sample (e.g., from the same type of tissue sample) from thepatient prior to administration of the compound indicates that thepatient is responsive to the compound and that the compound may be or isbeneficial and/or of therapeutic value to the patient; and (2) no changeor no substantial change in the amount of mRNA that is transcribed fromthe SMN1 and/or SMN2 gene and does not include exon 7 of SMN1 and/orSMN2 in the patient sample relative to the amount of mRNA that istranscribed from the SMN1 and/or SMN2 gene and does not include exon 7of SMN1 and/or SMN2 in an analogous sample (e.g., from the same type oftissue sample) from the patient prior to administration of the compoundindicates that the patient is not responsive to the compound and thatthe compound is not beneficial and/or of therapeutic value to thepatient. In certain embodiments, the patient's response is assessed 1hour, 2 hours, 4 hours, 8 hours, 12 hours, 16 hours, 20 hours, 1 day, 2days, 3 days, 5 days, 7 days, 14 days, 28 days, 1 month, 2 months, 3months, 6 months, 9 months, 12 months or more after administration of acompound, such as a compound of Formula (I) or a form thereof asdescribed herein.

In a specific embodiment, provided herein is a method for assessing anSMA patient's response to a compound, comprising: (a) contacting an SMApatient sample (e.g., blood sample or tissue sample) or a sample derivedfrom an SMA patient (e.g., a blood sample or tissue sample that has beenprocessed to extract RNA) with a forward SMN primer described below(e.g., SEQ ID NO. 11 or 13) and/or a reverse SMN primer described herein(e.g., SEQ ID NO. 9 or 12) along with applicable components for e.g.,RT-PCR (e.g., endpoint RT-PCR and/or RT-qPCR), PCR (e.g., qPCR) orrolling circle amplification, wherein the sample is from or derived froman SMA patient administered a compound (e.g., a compound of Formula (I)or a form thereof as described herein); and (b) detecting the amount ofmRNA that is transcribed from the SMN1 and/or SMN2 gene and includesexon 7 of SMN1 and/or SMN2 and the amount of mRNA that is transcribedfrom the SMN1 and/or SMN2 gene and does not include exon 7 of SMN1and/or SMN2, wherein (1)(i) an increase in the amount of mRNA that istranscribed from the SMN1 and/or SMN2 gene and includes exon 7 of SMN1and/or SMN2 in the patient sample relative to the amount of mRNA that istranscribed from the SMN1 and/or SMN2 gene and includes exon 7 of SMN1and/or SMN2 in an analogous sample (e.g., from the same type of tissuesample) from the patient prior to administration of the compound, and(ii) a decrease in the amount of mRNA that is transcribed from the SMN1and/or SMN2 gene and does not include exon 7 of SMN1 and/or SMN2 in thepatient sample relative to the amount of mRNA that is transcribed fromthe SMN1 and/or SMN2 gene and does not include exon 7 of SMN1 and/orSMN2 in an analogous sample (e.g., from the same type of tissue sample)from the patient prior to administration of the compound, indicate thatthe patient is responsive to the compound and that the compound may beor is beneficial and/or of therapeutic value to the patient; and (2)(i)no change or no substantial change in the amount of mRNA that istranscribed from the SMN1 and/or SMN2 gene and includes exon 7 of SMN1and/or SMN2 in the patient sample relative to the amount of mRNA that istranscribed from the SMN1 and/or SMN2 gene and includes exon 7 of SMN1and/or SMN2 in an analogous sample (e.g., the same type of tissuesample) from the patient prior to administration of the compound, and(ii) no change or no substantial change in the amount of mRNA that istranscribed from the SMN1 and/or SMN2 gene and does not include exon 7of SMN1 and/or SMN2 in the patient sample relative to the amount of mRNAthat is transcribed from the SMN1 and/or SMN2 gene and does not includeexon 7 of SMN1 and/or SMN2 in an analogous sample (e.g., the same typeof tissue sample) from the patient prior to administration of thecompound, indicates that the patient is not responsive to the compoundand that the compound is not beneficial and/or of therapeutic value tothe patient. In certain embodiments, the patient's response is assessed1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 16 hours, 20 hours, 1 day,2 days, 3 days, 5 days, 7 days, 14 days, 28 days, 1 month, 2 months, 3months, 6 months, 9 months, 12 months or more after administration of acompound, such as a compound of Formula (I) or a form thereof asdescribed herein.

In another specific embodiment, provided herein is a method forassessing an SMA patient's response to a compound, comprising: (a)administering a compound to an SMA patient; (b) contacting a sample(e.g., blood sample or tissue sample) obtained or derived from thepatient with a forward SMN primer described below (e.g., SEQ ID NO. 11or 13) and/or a reverse SMN primer described herein (e.g., SEQ ID NO. 9or 12) along with applicable components for e.g., RT-PCR (e.g., endpointRT-PCR and/or RT-qPCR), PCR (e.g., qPCR) or rolling circleamplification; and (c) detecting the amount of mRNA that is transcribedfrom the SMN1 and/or SMN2 gene and includes exon 7 of SMN1 and/or SMN2and the amount of mRNA that is transcribed from the SMN1 and/or SMN2gene and does not include exon 7 of SMN1 and/or SMN2, wherein (1)(i) anincrease in the amount of mRNA that is transcribed from the SMN1 and/orSMN2 gene and includes exon 7 of SMN1 and/or SMN2 in the patient samplerelative to the amount of mRNA that is transcribed from the SMN1 and/orSMN2 gene and includes exon 7 of SMN1 and/or SMN2 in an analogous sample(e.g., from the same type of tissue sample) from the patient prior toadministration of the compound, and (ii) a decrease in the amount ofmRNA that is transcribed from the SMN1 and/or SMN2 gene and does notinclude exon 7 of SMN1 and/or SMN2 in the patient sample relative to theamount of mRNA that is transcribed from the SMN1 and/or SMN2 gene anddoes not include exon 7 of SMN1 and/or SMN2 in an analogous sample(e.g., from the same type of tissue sample) from the patient prior toadministration of the compound, indicate that the patient is responsiveto the compound and that the compound may be or is beneficial and/or oftherapeutic value to the patient; and (2)(i) no change or no substantialchange in the amount of mRNA that is transcribed from the SMN1 and/orSMN2 gene and includes exon 7 of SMN1 and/or SMN2 in the patient samplerelative to the amount of mRNA that is transcribed from the SMN1 and/orSMN2 gene and includes exon 7 of SMN1 and/or SMN2 in an analogous sample(e.g., the same type of tissue sample) from the patient prior toadministration of the compound, and (ii) no change or no substantialchange in the amount of mRNA that is transcribed from the SMN1 and/orSMN2 gene and does not include exon 7 of SMN1 and/or SMN2 in the patientsample relative to the amount of mRNA that is transcribed from the SMN1and/or SMN2 gene and does not include exon 7 of SMN1 and/or SMN2 in ananalogous sample (e.g., the same type of tissue sample) from the patientprior to administration of the compound, indicate that the patient isnot responsive to the compound and that the compound is not beneficialand/or of therapeutic value to the patient. In certain embodiments, thepatient's response is assessed 1 hour, 2 hours, 4 hours, 8 hours, 12hours, 16 hours, 20 hours, 1 day, 2 days, 3 days, 5 days, 7 days, 14days, 28 days, 1 month, 2 months, 3 months, 6 months, 9 months, 12months or more after administration of a compound, such as a compound ofFormula (I) or a form thereof as described herein.

In a specific embodiment, provided herein is a method for assessing anSMA patient's response to a compound, comprising: (a) contacting an SMApatient sample (e.g., blood sample or tissue sample) or a sample derivedfrom an SMA patient (e.g., a blood sample or tissue sample that has beenprocessed to extract RNA) with an SMN probe (e.g., SEQ ID NO. 10) alongwith applicable components for e.g., RT-PCR (e.g., endpoint RT-PCRand/or RT-qPCR), PCR (e.g., qPCR) or rolling circle amplification,wherein the sample is from or derived from an SMA patient administered acompound (e.g., a compound of Formula (I) or a form thereof as describedherein); and (b) detecting the amount of mRNA that is transcribed fromthe SMN1 and/or SMN2 gene and includes exon 7 of SMN1 and/or SMN2 andthe amount of mRNA that is transcribed from the SMN1 and/or SMN2 geneand does not include exon 7 of SMN1 and/or SMN2, wherein (1)(i) anincrease in the amount of mRNA that is transcribed from the SMN1 and/orSMN2 gene and includes exon 7 of SMN1 and/or SMN2 in the patient samplerelative to the amount of mRNA that is transcribed from the SMN1 and/orSMN2 gene and includes exon 7 of SMN1 and/or SMN2 in an analogous sample(e.g., from the same type of tissue sample) from the patient prior toadministration of the compound, and (ii) a decrease in the amount ofmRNA that is transcribed from the SMN1 and/or SMN2 gene and does notinclude exon 7 of SMN1 and/or SMN2 in the patient sample relative to theamount of mRNA that is transcribed from the SMN1 and/or SMN2 gene anddoes not include exon 7 of SMN1 and/or SMN2 in an analogous sample(e.g., from the same type of tissue sample) from the patient prior toadministration of the compound, indicate that the patient is responsiveto the compound and that the compound may be or is beneficial and/or oftherapeutic value to the patient; and (2)(i) no change or no substantialchange in the amount of mRNA that is transcribed from the SMN1 and/orSMN2 gene and includes exon 7 of SMN1 and/or SMN2 in the patient samplerelative to the amount of mRNA that is transcribed from the SMN1 and/orSMN2 gene and includes exon 7 of SMN1 and/or SMN2 in an analogous sample(e.g., the same type of tissue sample) from the patient prior toadministration of the compound, and (ii) no change or no substantialchange in the amount of mRNA that is transcribed from the SMN1 and/orSMN2 gene and does not include exon 7 of SMN1 and/or SMN2 in the patientsample relative to the amount of mRNA that is transcribed from the SMN1and/or SMN2 gene and does not include exon 7 of SMN1 and/or SMN2 in ananalogous sample (e.g., the same type of tissue sample) from the patientprior to administration of the compound, indicate that the patient isnot responsive to the compound and that the compound is not beneficialand/or of therapeutic value to the patient. In certain embodiments, thepatient's response is assessed 1 hour, 2 hours, 4 hours, 8 hours, 12hours, 16 hours, 20 hours, 1 day, 2 days, 3 days, 5 days, 7 days, 14days, 28 days, 1 month, 2 months, 3 months, 6 months, 9 months, 12months or more after administration of a compound, such as a compound ofFormula (I) or a form thereof as described herein.

In another specific embodiment, provided herein is a method forassessing an SMA patient's response to a compound, comprising: (a)administering a compound to an SMA patient; (b) contacting a sample(e.g., blood sample or tissue sample) obtained or derived from thepatient with an SMN probe (e.g., SEQ ID NO. 10) along with applicablecomponents for e.g., RT-PCR (e.g., endpoint RT-PCR and/or RT-qPCR), PCR(e.g., qPCR) or rolling circle amplification; and (c) detecting theamount of mRNA that is transcribed from the SMN1 and/or SMN2 gene andincludes exon 7 of SMN1 and/or SMN2 and the amount of mRNA that istranscribed from the SMN1 and/or SMN2 gene and does not include exon 7of SMN1 and/or SMN2, wherein (1)(i) an increase in the amount of mRNAthat is transcribed from the SMN1 and/or SMN2 gene and includes exon 7of SMN1 and/or SMN2 in the patient sample relative to the amount of mRNAthat is transcribed from the SMN1 and/or SMN2 gene and includes exon 7of SMN1 and/or SMN2 in an analogous sample (e.g., from the same type oftissue sample) from the patient prior to administration of the compound,and (ii) a decrease in the amount of mRNA that is transcribed from theSMN1 and/or SMN2 gene and does not include exon 7 of SMN1 and/or SMN2 inthe patient sample relative to the amount of mRNA that is transcribedfrom the SMN1 and/or SMN2 gene and does not include exon 7 of SMN1and/or SMN2 in an analogous sample (e.g., from the same type of tissuesample) from the patient prior to administration of the compound,indicate that the patient is responsive to the compound and that thecompound may be or is beneficial and/or of therapeutic value to thepatient; and (2)(i) no change or no substantial change in the amount ofmRNA that is transcribed from the SMN1 and/or SMN2 gene and includesexon 7 of SMN1 and/or SMN2 in the patient sample relative to the amountof mRNA that is transcribed from the SMN1 and/or SMN2 gene and includesexon 7 of SMN1 and/or SMN2 in an analogous sample (e.g., the same typeof tissue sample) from the patient prior to administration of thecompound, and (ii) no change or no substantial change in the amount ofmRNA that is transcribed from the SMN1 and/or SMN2 gene and does notinclude exon 7 of SMN1 and/or SMN2 in the patient sample relative to theamount of mRNA that is transcribed from the SMN1 and/or SMN2 gene anddoes not include exon 7 of SMN1 and/or SMN2 in an analogous sample(e.g., the same type of tissue sample) from the patient prior toadministration of the compound, indicate that the patient is notresponsive to the compound and that the compound is not beneficialand/or of therapeutic value to the patient. In certain embodiments, thepatient's response is assessed 1 hour, 2 hours, 4 hours, 8 hours, 12hours, 16 hours, 20 hours, 1 day, 2 days, 3 days, 5 days, 7 days, 14days, 28 days, 1 month, 2 months, 3 months, 6 months, 9 months, 12months or more after administration of a compound, such as a compound ofFormula (I) or a form thereof as described herein.

In a specific embodiment, provided herein is a method for assessing anSMA patient's response to a compound, comprising: (a) contacting an SMApatient sample (e.g., blood sample or tissue sample) or a sample derivedfrom an SMA patient (e.g., a blood sample or tissue sample that has beenprocessed to extract RNA) with a forward SMN primer described below(e.g., SEQ ID NO. 11 or 13) and/or a reverse SMN primer described herein(e.g., SEQ ID NO. 9 or 12) and/or an SMN probe (e.g., SEQ ID NO. 10)along with applicable components for e.g., RT-PCR (e.g., endpoint RT-PCRand/or RT-qPCR) or PCR (e.g., qPCR), wherein the sample is from orderived from an SMA patient administered a compound (e.g., a compound ofFormula (I) or a form thereof as described herein); and (b) detectingthe amount of mRNA that is transcribed from the SMN1 and/or SMN2 geneand includes exon 7 of SMN1 and/or SMN2 and the amount of mRNA that istranscribed from the SMN1 and/or SMN2 gene and does not include exon 7of SMN1 and/or SMN2, wherein (1)(i) an increase in the amount of mRNAthat is transcribed from the SMN1 and/or SMN2 gene and includes exon 7of SMN1 and/or SMN2 in the patient sample relative to the amount of mRNAthat is transcribed from the SMN1 and/or SMN2 gene and includes exon 7of SMN1 and/or SMN2 in an analogous sample (e.g., from the same type oftissue sample) from the patient prior to administration of the compound,and (ii) a decrease in the amount of mRNA that is transcribed from theSMN1 and/or SMN2 gene and does not include exon 7 of SMN1 and/or SMN2 inthe patient sample relative to the amount of mRNA that is transcribedfrom the SMN1 and/or SMN2 gene and does not include exon 7 of SMN1and/or SMN2 in an analogous sample (e.g., from the same type of tissuesample) from the patient prior to administration of the compound,indicate that the patient is responsive to the compound and that thecompound may be or is beneficial and/or of therapeutic value to thepatient; and (2)(i) no change or no substantial change in the amount ofmRNA that is transcribed from the SMN1 and/or SMN2 gene and includesexon 7 of SMN1 and/or SMN2 in the patient sample relative to the amountof mRNA that is transcribed from the SMN1 and/or SMN2 gene and includesexon 7 of SMN1 and/or SMN2 in an analogous sample (e.g., the same typeof tissue sample) from the patient prior to administration of thecompound, and (ii) no change or no substantial change in the amount ofmRNA that is transcribed from the SMN1 and/or SMN2 gene and does notinclude exon 7 of SMN1 and/or SMN2 in the patient sample relative to theamount of mRNA that is transcribed from the SMN1 and/or SMN2 gene anddoes not include exon 7 of SMN1 and/or SMN2 in an analogous sample(e.g., the same type of tissue sample) from the patient prior toadministration of the compound, indicate that the patient is notresponsive to the compound and that the compound is not beneficialand/or of therapeutic value to the patient. In certain embodiments, thepatient's response is assessed 1 hour, 2 hours, 4 hours, 8 hours, 12hours, 16 hours, 20 hours, 1 day, 2 days, 3 days, 5 days, 7 days, 14days, 28 days, 1 month, 2 months, 3 months, 6 months, 9 months, 12months or more after administration of a compound, such as a compound ofFormula (I) or a form thereof as described herein.

In another specific embodiment, provided herein is a method forassessing an SMA patient's response to a compound, comprising: (a)administering a compound to an SMA patient; (b) contacting a sample(e.g., blood sample or tissue sample) obtained or derived from thepatient with a forward SMN primer described below (e.g., SEQ ID NO. 11or 13) and/or a reverse SMN primer described herein (e.g., SEQ ID NO. 9or 12) and/or an SMN probe (e.g., SEQ ID NO. 10) along with applicablecomponents for, e.g., RT-PCR (e.g., endpoint RT-PCR and/or RT-qPCR), PCR(e.g., qPCR) or rolling circle amplification; and (c) detecting theamount of mRNA that is transcribed from the SMN1 and/or SMN2 gene andincludes exon 7 of SMN1 and/or SMN2 and the amount of mRNA that istranscribed from the SMN1 and/or SMN2 gene and does not include exon 7of SMN1 and/or SMN2, wherein (1)(i) an increase in the amount of mRNAthat is transcribed from the SMN1 and/or SMN2 gene and includes exon 7of SMN1 and/or SMN2 in the patient sample relative to the amount of mRNAthat is transcribed from the SMN1 and/or SMN2 gene and includes exon 7of SMN1 and/or SMN2 in an analogous sample (e.g., from the same type oftissue sample) from the patient prior to administration of the compound,and (ii) a decrease in the amount of mRNA that is transcribed from theSMN1 and/or SMN2 gene and does not include exon 7 of SMN1 and/or SMN2 inthe patient sample relative to the amount of mRNA that is transcribedfrom the SMN1 and/or SMN2 gene and does not include exon 7 of SMN1and/or SMN2 in an analogous sample (e.g., from the same type of tissuesample) from the patient prior to administration of the compound,indicate that the SMN1 and/or patient is responsive to the compound andthat the compound may be or is beneficial and/or of therapeutic value tothe patient; and (2)(i) no change or no substantial change in the amountof mRNA that is transcribed from the SMN1 and/or SMN2 gene and includesexon 7 of SMN1 and/or SMN2 in the patient sample relative to the amountof mRNA that is transcribed from the SMN1 and/or SMN2 gene and includesexon 7 of SMN1 and/or SMN2 in an analogous sample (e.g., the same typeof tissue sample) from the patient prior to administration of thecompound, and (ii) no change or no substantial change in the amount ofmRNA that is transcribed from the SMN1 and/or SMN2 gene and does notinclude exon 7 of SMN1 and/or SMN2 in the patient sample relative to theamount of mRNA that is transcribed from the SMN1 and/or SMN2 gene anddoes not include exon 7 of SMN1 and/or SMN2 in an analogous sample(e.g., the same type of tissue sample) from the patient prior toadministration of the compound, indicate that the patient is notresponsive to the compound and that the compound is not beneficialand/or of therapeutic value to the patient. In certain embodiments, thepatient's response is assessed 1 hour, 2 hours, 4 hours, 8 hours, 12hours, 16 hours, 20 hours, 1 day, 2 days, 3 days, 5 days, 7 days, 14days, 28 days, 1 month, 2 months, 3 months, 6 months, 9 months, 12months or more after administration of a compound, such as a compound ofFormula (I) or a form thereof as described herein.

In a specific embodiment, provided herein is a method for monitoring anSMA patient's responsiveness to a compound, comprising: (a) contactingan SMA patient sample (e.g., blood sample or tissue sample) or a samplederived from an SMA patient (e.g., a blood sample or tissue sample thathas been processed to extract RNA) with a forward SMN primer describedbelow (e.g., SEQ ID NO. 1, 7, 11 or 13) and/or a reverse SMN primerdescribed herein (e.g., SEQ ID NO. 9 or 12) along with applicablecomponents for e.g., RT-PCR (e.g., endpoint RT-PCR and/or RT-qPCR), PCR(e.g., qPCR) or rolling circle amplification, wherein the sample is fromor derived from an SMA patient administered a compound (e.g., a compoundof Formula (I) or a form thereof as described herein); and (b) detectingthe amount of mRNA that is transcribed from the SMN1 and/or SMN2 geneand includes exon 7 of SMN1 and/or SMN2, wherein (1) an increase in theamount of mRNA that is transcribed from the SMN1 and/or SMN2 gene andincludes exon 7 of SMN1 and/or SMN2 in the patient sample relative tothe amount of mRNA that is transcribed from the SMN1 and/or SMN2 geneand includes exon 7 of SMN1 and/or SMN2 in an analogous sample (e.g.,from the same type of tissue sample) from the patient prior to theadministration of the compound or a certain number of doses of thecompound, or a certain earlier date indicates that the patient isresponsive to the compound and that the compound may be or is beneficialand/or of therapeutic value to the patient; and (2) no change or nosubstantial change in the amount of mRNA that is transcribed from theSMN1 and/or SMN2 gene and includes exon 7 of SMN1 and/or SMN2 in thepatient sample relative to the amount of mRNA that is transcribed fromthe SMN1 and/or SMN2 gene and includes exon 7 of SMN1 and/or SMN2 in ananalogous sample (e.g., from the same type of tissue sample) from thepatient prior to the administration of the compound or a certain numberof doses of the compound, or a certain earlier date indicates that thepatient is not responsive to the compound and that the compound is notbeneficial and/or of therapeutic value to the patient. In certainembodiments, the patient's response is monitored 1 hour, 2 hours, 4hours, 8 hours, 12 hours, 16 hours, 20 hours, 1 day, 2 days, 3 days, 4days, 5 days, 7 days, 14 days, 28 days, 1 month, 2 months, 3 months, 6months, 9 months, 12 months or more after administration of a compound,such as of Formula (I) or a form thereof as described herein. In someembodiments, the patient's response is monitored after the patient hasreceived 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25 or more doses of a compound, such as acompound of Formula (I) or a form thereof as described herein. In someembodiments, the patient's response is monitored after theadministration of 1-5, 5-10, 10-15, 15-20, 20-30, 30-40, 40-50, or50-100 doses of a compound, such as a compound of Formula (I) or a formthereof as described herein. In some embodiments, the patient's responseis monitored over a period of days, weeks, months or years during orafter the continuous administration of a compound, such as a compound ofFormula (I) or a form thereof as described herein.

In another specific embodiment, provided herein is a method formonitoring an SMA patient's responsiveness to a compound, comprising:(a) administering a compound to an SMA patient; (b) contacting a sample(e.g., blood sample or tissue sample) obtained or derived from thepatient with a forward SMN primer described below (e.g., SEQ ID NO. 1,7, 11 or 13) and/or a reverse SMN primer described herein (e.g., SEQ IDNO. 9 or 12) along with applicable components for, e.g., RT-PCR (e.g.,endpoint RT-PCR and/or RT-qPCR), PCR (e.g., qPCR) or rolling circleamplification; and (c) detecting the amount of mRNA that is transcribedfrom the SMN1 and/or SMN2 gene and includes exon 7 of SMN1 and/or SMN2,wherein (1) an increase in the amount of mRNA that is transcribed fromthe SMN1 and/or SMN2 gene and includes exon 7 of SMN1 and/or SMN2 in thepatient sample relative to the amount of mRNA that is transcribed fromthe SMN1 and/or SMN2 gene and includes exon 7 of SMN1 and/or SMN2 in ananalogous sample (e.g., from the same type of tissue sample) from thepatient prior to the administration of the compound or a certain numberof doses of the compound, or a certain earlier date indicates that thepatient is responsive to the compound and that the compound may be or isbeneficial and/or of therapeutic value to the patient; and (2) no changeor no substantial change in the amount of mRNA that is transcribed fromthe SMN1 and/or SMN2 gene and includes exon 7 of SMN1 and/or SMN2 in thepatient sample relative to the amount of mRNA that is transcribed fromthe SMN1 and/or SMN2 gene and includes exon 7 of SMN1 and/or SMN2 in ananalogous sample (e.g., from the same type of tissue sample) from thepatient prior to the administration of the compound or a certain numberof doses of the compound, or a certain earlier date indicates that thepatient is not responsive to the compound and that the compound is notbeneficial and/or of therapeutic value to the patient. In certainembodiments, the patient's response is monitored 1 hour, 2 hours, 4hours, 8 hours, 12 hours, 16 hours, 20 hours, 1 day, 2 days, 3 days, 4days, 5 days, 7 days, 14 days, 28 days, 1 month, 2 months, 3 months, 6months, 9 months, 12 months or more after administration of a compound,such as a compound of Formula (I) or a form thereof as described herein.In some embodiments, the patient's response is monitored after thepatient has received 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more doses of a compound, suchas a compound of Formula (I) or a form thereof as described herein. Insome embodiments, the patient's response is monitored after theadministration of 1-5, 5-10, 10-15, 15-20, 20-30, 30-40, 40-50, or50-100 doses of a compound, such as a compound of Formula (I) or a formthereof as described herein. In some embodiments, the patient's responseis monitored over a period of days, weeks, months or years during orafter the continuous administration of a compound, such as a compound ofFormula (I) or a form thereof as described herein.

In a specific embodiment, provided herein is a method for monitoring anSMA patient's responsiveness to a compound, comprising: (a) contactingan SMA patient sample (e.g., blood sample or tissue sample) or a samplederived from an SMA patient (e.g., a blood sample or tissue sample thathas been processed to extract RNA) with a forward SMN primer describedbelow (e.g., SEQ ID NO. 1, 7, 11 or 13) and/or a reverse SMN primerdescribed herein (e.g., SEQ ID NO. 9 or 12) and/or an SMN probe (e.g.,SEQ ID NO. 3 or 10) along with applicable components for e.g., RT-PCR(e.g., endpoint RT-PCR and/or RT-qPCR), PCR (e.g., qPCR) or rollingcircle amplification, wherein the sample is from or derived from an SMApatient administered a compound (e.g., a compound of Formula (I) or aform thereof as described herein); and (b) detecting the amount of mRNAthat is transcribed from the SMN1 and/or SMN2 gene and includes exon 7of SMN1 and/or SMN2, wherein (1) an increase in the amount of mRNA thatis transcribed from the SMN1 and/or SMN2 gene and includes exon 7 ofSMN1 and/or SMN2 in the patient sample relative to the amount of mRNAthat is transcribed from the SMN1 and/or SMN2 gene and includes exon 7of SMN1 and/or SMN2 in an analogous sample (e.g., from the same type oftissue sample) from the patient prior to the administration of thecompound or a certain number of doses of the compound, or a certainearlier date indicates that the patient is responsive to the compoundand that the compound may be or is beneficial and/or of therapeuticvalue to the patient; and (2) no change or no substantial change in theamount of mRNA that is transcribed from the SMN1 and/or SMN2 gene andincludes exon 7 of SMN1 and/or SMN2 in the patient sample relative tothe amount of mRNA that is transcribed from the SMN1 and/or SMN2 geneand includes exon 7 of SMN1 and/or SMN2 in an analogous sample (e.g.,from the same type of tissue sample) from the patient prior to theadministration of the compound or a certain number of doses of thecompound, or a certain earlier date indicates that the patient is notresponsive to the compound and that the compound is not beneficialand/or of therapeutic value to the patient. In certain embodiments, thepatient's response is monitored 1 hour, 2 hours, 4 hours, 8 hours, 12hours, 16 hours, 20 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 7days, 14 days, 28 days, 1 month, 2 months, 3 months, 6 months, 9 months,12 months or more after administration of a compound, such as of Formula(I) or a form thereof as described herein. In some embodiments, thepatient's response is monitored after the patient has received 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25 or more doses of a compound, such as a compound of Formula(I) or a form thereof as described herein. In some embodiments, thepatient's response is monitored after the administration of 1-5, 5-10,10-15, 15-20, 20-30, 30-40, 40-50, or 50-100 doses of a compound, suchas a compound of Formula (I) or a form thereof as described herein. Insome embodiments, the patient's response is monitored over a period ofdays, weeks, months or years during or after the continuousadministration of a compound, such as a compound of Formula (I) or aform thereof as described herein.

In another specific embodiment, provided herein is a method formonitoring an SMA patient's responsiveness to a compound, comprising:(a) administering a compound to an SMA patient; (b) contacting a sample(e.g., blood sample or tissue sample) obtained or derived from thepatient with a forward SMN primer described below (e.g., SEQ ID NO. 1,7, 11 or 13) and/or a reverse SMN primer described herein (e.g., SEQ IDNO. 9 or 12) and/or an SMN probe (e.g., SEQ ID NO. 3 or 10) along withapplicable components for, e.g., RT-PCR (e.g., endpoint RT-PCR and/orRT-qPCR), PCR (e.g., qPCR) or rolling circle amplification; and (c)detecting the amount of mRNA that is transcribed from the SMN1 and/orSMN2 gene and includes exon 7 of SMN1 and/or SMN2, wherein (1) anincrease in the amount of mRNA that is transcribed from the SMN1 and/orSMN2 gene and includes exon 7 of SMN1 and/or SMN2 in the patient samplerelative to the amount of mRNA that is transcribed from the SMN1 and/orSMN2 gene and includes exon 7 of SMN1 and/or SMN2 in an analogous sample(e.g., from the same type of tissue sample) from the patient prior tothe administration of the compound or a certain number of doses of thecompound, or a certain earlier date indicates that the patient isresponsive to the compound and that the compound may be or is beneficialand/or of therapeutic value to the patient; and (2) no change or nosubstantial change in the amount of mRNA that is transcribed from theSMN1 and/or SMN2 gene and includes exon 7 of SMN1 and/or SMN2 in thepatient sample relative to the amount of mRNA that is transcribed fromthe SMN1 and/or SMN2 gene and includes exon 7 of SMN1 and/or SMN2 in ananalogous sample (e.g., from the same type of tissue sample) from thepatient prior to the administration of the compound or a certain numberof doses of the compound, or a certain earlier date indicates that thepatient is not responsive to the compound and that the compound is notbeneficial and/or of therapeutic value to the patient. In certainembodiments, the patient's response is monitored 1 hour, 2 hours, 4hours, 8 hours, 12 hours, 16 hours, 20 hours, 1 day, 2 days, 3 days, 4days, 5 days, 7 days, 14 days, 28 days, 1 month, 2 months, 3 months, 6months, 9 months, 12 months or more after administration of a compound,such as a compound of Formula (I) or a form thereof as described herein.In some embodiments, the patient's response is monitored after thepatient has received 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more doses of a compound, suchas a compound of Formula (I) or a form thereof as described herein. Insome embodiments, the patient's response is monitored after theadministration of 1-5, 5-10, 10-15, 15-20, 20-30, 30-40, 40-50, or50-100 doses of a compound, such as a compound of Formula (I) or a formthereof as described herein. In some embodiments, the patient's responseis monitored over a period of days, weeks, months or years during orafter the continuous administration of a compound, such as a compound ofFormula (I) or a form thereof as described herein.

In a specific embodiment, provided herein is a method for monitoring anSMA patient's responsiveness to a compound, comprising: (a) contactingan SMA patient sample (e.g., blood sample or tissue sample) or a samplederived from an SMA patient (e.g., a blood sample or tissue sample thathas been processed to extract RNA) with a forward SMN primer describedbelow (e.g., SEQ ID NO. 8, 11 or 13) and/or a reverse SMN primerdescribed herein (e.g., SEQ ID NO. 9 or 12) along with applicablecomponents for, e.g., RT-PCR (e.g., endpoint RT-PCR and/or RT-qPCR), PCR(e.g., qPCR) or rolling circle amplification, wherein the sample is fromor derived from an SMA patient administered a compound (e.g., a compoundof Formula (I) or a form thereof as described herein); and (b) detectingthe amount of mRNA that is transcribed from the SMN1 and/or SMN2 geneand does not include exon 7 of SMN1 and/or SMN2, wherein (1) a decreasein the amount of mRNA that is transcribed from the SMN1 and/or SMN2 geneand does not include exon 7 of SMN1 and/or SMN2 in the patient samplerelative to the amount of mRNA that is transcribed from the SMN1 and/orSMN2 gene and does not include exon 7 of SMN1 and/or SMN2 in ananalogous sample (e.g., from the same type of tissue sample) from thepatient prior to the administration of the compound or a certain numberof doses of the compound, or a certain earlier date indicates that thepatient is responsive to the compound and that the compound may be or isbeneficial and/or of therapeutic value to the patient; and (2) no changeor no substantial change in the amount of mRNA that is transcribed fromthe SMN1 and/or SMN2 gene and does not include exon 7 of SMN1 and/orSMN2 in the patient sample relative to the amount of mRNA that istranscribed from the SMN1 and/or SMN2 gene and does not include exon 7of SMN1 and/or SMN2 in an analogous sample (e.g., from the same type oftissue sample) from the patient prior to the administration of thecompound or a certain number of doses of the compound, or a certainearlier date indicates that the patient is not responsive to thecompound and that the compound is not beneficial and/or of therapeuticvalue to the patient. In certain embodiments, the patient's response ismonitored 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 16 hours, 20hours, 1 day, 2 days, 3 days, 4 days, 5 days, 7 days, 14 days, 28 days,1 month, 2 months, 3 months, 6 months, 9 months, 12 months or more afteradministration of a compound, such as a compound of Formula (I) or aform thereof as described herein. In some embodiments, the patient'sresponse is monitored after the patient has received 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25or more doses of a compound, such as a compound of Formula (I) or a formthereof as described herein. In some embodiments, the patient's responseis monitored after the administration of 1-5, 5-10, 10-15, 15-20, 20-30,30-40, 40-50, or 50-100 doses of a compound, such as a compound ofFormula (I) or a form thereof as described herein. In some embodiments,the patient's response is monitored over a period of days, weeks, monthsor years during or after the continuous administration of a compound,such as a compound of Formula (I) or a form thereof as described herein.

In another specific embodiment, provided herein is a method formonitoring an SMA patient's responsiveness to a compound, comprising:(a) administering a compound to an SMA patient; (b) contacting a sample(e.g., blood sample or tissue sample) obtained or derived from thepatient with a forward SMN primer described below (e.g., SEQ ID NO. 8,11 or 13) and/or a reverse SMN primer described herein (e.g., SEQ ID NO.9 or 12) along with applicable components for, e.g., RT-PCR (e.g.,endpoint RT-PCR and/or RT-qPCR), PCR (e.g., qPCR) or rolling circleamplification; and (c) detecting the amount of mRNA that is transcribedfrom the SMN1 and/or SMN2 gene and does not include exon 7 of SMN1and/or SMN2, wherein (1) a decrease in the amount of mRNA that istranscribed from the SMN1 and/or SMN2 gene and does not include exon 7of SMN1 and/or SMN2 in the patient sample relative to the amount of mRNAthat is transcribed from the SMN1 and/or SMN2 gene and does not includeexon 7 of SMN1 and/or SMN2 in an analogous sample (e.g., from the sametype of tissue sample) from the patient prior to the administration ofthe compound or a certain number of doses of the compound, or a certainearlier date indicates that the patient is responsive to the compoundand that the compound may be or is beneficial and/or of therapeuticvalue to the patient; and (2) no change or no substantial change in theamount of mRNA that is transcribed from the SMN1 and/or SMN2 gene anddoes not include exon 7 of SMN1 and/or SMN2 in the patient samplerelative to the amount of mRNA that is transcribed from the SMN1 and/orSMN2 gene and does not include exon 7 of SMN1 and/or SMN2 in ananalogous sample (e.g., from the same type of tissue sample) from thepatient prior to the administration of the compound or a certain numberof doses of the compound, or a certain earlier date indicates that thepatient is not responsive to the compound and that the compound is notbeneficial and/or of therapeutic value to the patient. In certainembodiments, the patient's response is monitored 1 hour, 2 hours, 4hours, 8 hours, 12 hours, 16 hours, 20 hours, 1 day, 2 days, 3 days, 4days, 5 days, 7 days, 14 days, 28 days, 1 month, 2 months, 3 months, 6months, 9 months, 12 months or more after administration of a compound,such as a compound of Formula (I) or a form thereof as described herein.In some embodiments, the patient's response is monitored after thepatient has received 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more doses of a compound, suchas a compound of Formula (I) or a form thereof as described herein. Insome embodiments, the patient's response is monitored after theadministration of 1-5, 5-10, 10-15, 15-20, 20-30, 30-40, 40-50, or50-100 doses of a compound, such as a compound of Formula (I) or a formthereof as described herein. In some embodiments, the patient's responseis monitored continuous administration of a compound over a period ofdays, weeks, months or years, such as a compound of Formula (I) or aform thereof as described herein.

In a specific embodiment, provided herein is a method for monitoring anSMA patient's responsiveness to a compound, comprising: (a) contactingan SMA patient sample (e.g., blood sample or tissue sample) or a samplederived from an SMA patient (e.g., a blood sample or tissue sample thathas been processed to extract RNA) with a forward SMN primer describedbelow (e.g., SEQ ID NO. 8, 11 or 13) and/or a reverse SMN primerdescribed herein (e.g., SEQ ID NO. 9 or 12) and/or an SMN probe (e.g.,SEQ ID NO. 10) along with applicable components for, e.g., RT-PCR (e.g.,endpoint RT-PCR and/or RT-qPCR), PCR (e.g., qPCR) or rolling circleamplification, wherein the sample is from or derived from a patientadministered a compound (e.g., a compound of Formula (I) or a formthereof as described herein); and (b) detecting the amount of mRNA thatis transcribed from the SMN1 and/or SMN2 gene and does not include exon7 of SMN1 and/or SMN2, wherein (1) a decrease in the amount of mRNA thatis transcribed from the SMN1 and/or SMN2 gene and does not include exon7 of SMN1 and/or SMN2 in the patient sample relative to the amount ofmRNA that is transcribed from the SMN1 and/or SMN2 gene and does notinclude exon 7 of SMN1 and/or SMN2 in an analogous sample (e.g., fromthe same type of tissue sample) from the patient prior to theadministration of the compound or a certain number of doses of thecompound, or a certain earlier date indicates that the patient isresponsive to the compound and that the compound may be or is beneficialand/or of therapeutic value to the patient; and (2) no change or nosubstantial change in the amount of mRNA that is transcribed from theSMN1 and/or SMN2 gene and does not include exon 7 of SMN1 and/or SMN2 inthe patient sample relative to the amount of mRNA that is transcribedfrom the SMN1 and/or SMN2 gene and does not include exon 7 of SMN1and/or SMN2 in an analogous sample (e.g., from the same type of tissuesample) from the patient prior to the administration of the compound ora certain number of doses of the compound, or a certain earlier dateindicates that the patient is not responsive to the compound and thatthe compound is not beneficial and/or of therapeutic value to thepatient. In certain embodiments, the patient's response is monitored 1hour, 2 hours, 4 hours, 8 hours, 12 hours, 16 hours, 20 hours, 1 day, 2days, 3 days, 4 days, 5 days, 7 days, 14 days, 28 days, 1 month, 2months, 3 months, 6 months, 9 months, 12 months or more afteradministration of a compound, such as a compound of Formula (I) or aform thereof as described herein. In some embodiments, the patient'sresponse is monitored after the patient has received 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25or more doses of a compound, such as a compound of Formula (I) or a formthereof as described herein. In some embodiments, the patient's responseis monitored after the administration of 1-5, 5-10, 10-15, 15-20, 20-30,30-40, 40-50, or 50-100 doses of a compound, such as a compound ofFormula (I) or a form thereof as described herein. In some embodiments,the patient's response is monitored over a period of days, weeks, monthsor years during or after the continuous administration of a compound,such as a compound of Formula (I) or a form thereof as described herein.

In another specific embodiment, provided herein is a method formonitoring an SMA patient's responsiveness to a compound, comprising:(a) administering a compound to an SMA patient; (b) contacting a sample(e.g., blood sample or tissue sample) obtained or derived from thepatient with a forward SMN primer described below (e.g., SEQ ID NO. 8,11 or 13) and/or a reverse SMN primer described herein (e.g., SEQ ID NO.9 or 12) and/or an SMN probe (e.g., SEQ ID NO. 10) along with applicablecomponents for, e.g., RT-PCR (e.g., endpoint RT-PCR and/or RT-qPCR), PCR(e.g., qPCR) or rolling circle amplification; and (c) detecting theamount of mRNA that is transcribed from the SMN1 and/or SMN2 gene anddoes not include exon 7 of SMN1 and/or SMN2, wherein (1) a decrease inthe amount of mRNA that is transcribed from the SMN1 and/or SMN2 geneand does not include exon 7 of SMN1 and/or SMN2 in the patient samplerelative to the amount of mRNA that is transcribed from the SMN1 and/orSMN2 gene and does not include exon 7 of SMN1 and/or SMN2 in ananalogous sample (e.g., from the same type of tissue sample) from thepatient prior to the administration of the compound or a certain numberof doses of the compound, or a certain earlier date indicates that thepatient is responsive to the compound and that the compound may be or isbeneficial and/or of therapeutic value to the patient; and (2) no changeor no substantial change in the amount of mRNA that is transcribed fromthe SMN1 and/or SMN2 gene and does not include exon 7 of SMN1 and/orSMN2 in the patient sample relative to the amount of mRNA that istranscribed from the SMN1 and/or SMN2 gene and does not include exon 7of SMN1 and/or SMN2 in an analogous sample (e.g., from the same type oftissue sample) from the patient prior to the administration of thecompound or a certain number of doses of the compound, or a certainearlier date indicates that the patient is not responsive to thecompound and that the compound is not beneficial and/or of therapeuticvalue to the patient. In certain embodiments, the patient's response ismonitored 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 16 hours, 20hours, 1 day, 2 days, 3 days, 4 days, 5 days, 7 days, 14 days, 28 days,1 month, 2 months, 3 months, 6 months, 9 months, 12 months or more afteradministration of a compound, such as a compound of Formula (I) or aform thereof as described herein. In some embodiments, the patient'sresponse is monitored after the patient has received 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25or more doses of a compound, such as a compound of Formula (I) or a formthereof as described herein. In some embodiments, the patient's responseis monitored after the administration of 1-5, 5-10, 10-15, 15-20, 20-30,30-40, 40-50, or 50-100 doses of a compound, such as a compound ofFormula (I) or a form thereof as described herein. In some embodiments,the patient's response is monitored over a period of days, weeks, monthsor years during or after the continuous administration of a compound,such as a compound of Formula (I) or a form thereof as described herein.

In a specific embodiment, provided herein is a method for monitoring anSMA patient's response to a compound, comprising: (a) contacting an SMApatient sample (e.g., blood sample or tissue sample) or a sample derivedfrom an SMA patient (e.g., a blood sample or tissue sample that has beenprocessed to extract RNA) with a forward SMN primer described below(e.g., SEQ ID NO. 11 or 13) and/or a reverse SMN primer described herein(e.g., SEQ ID NO. 9 or 12) along with applicable components for, e.g.,RT-PCR (e.g., endpoint RT-PCR and/or RT-qPCR), PCR (e.g., qPCR) orrolling circle amplification, wherein the sample is from or derived froman SMA patient administered a compound (e.g., a compound of Formula (I)or a form thereof as described herein); and (b) detecting the amount ofmRNA that is transcribed from the SMN1 and/or SMN2 gene and includesexon 7 of SMN1 and/or SMN2 and the amount of mRNA that is transcribedfrom the SMN1 and/or SMN2 gene and does not include exon 7 of SMN1and/or SMN2, wherein (1)(i) an increase in the amount of mRNA that istranscribed from the SMN1 and/or SMN2 gene and includes exon 7 of SMN1and/or SMN2 in the patient sample relative to the amount of mRNA that istranscribed from the SMN1 and/or SMN2 gene and includes exon 7 of SMN1and/or SMN2 in an analogous sample (e.g., from the same type of tissuesample) from the patient prior to administration of the compound or acertain number of doses of the compound, or a certain earlier date, and(ii) a decrease in the amount of mRNA that is transcribed from the SMN1and/or SMN2 gene and does not include exon 7 of SMN1 and/or SMN2 in thepatient sample relative to the amount of mRNA that is transcribed fromthe SMN1 and/or SMN2 gene and does not include exon 7 of SMN1 and/orSMN2 in an analogous sample (e.g., from the same type of tissue sample)from the patient prior to administration of the compound or a certainnumber of doses of the compound, or a certain earlier date, indicatethat the patient is responsive to the compound and that the compound maybe or is beneficial and/or of therapeutic value to the patient; and(2)(i) no change or no substantial change in the amount of mRNA that istranscribed from the SMN1 and/or SMN2 gene and includes exon 7 of SMN1and/or SMN2 in the patient sample relative to the amount of mRNA that istranscribed from the SMN1 and/or SMN2 gene and includes exon 7 of SMN1and/or SMN2 in an analogous sample (e.g., the same type of tissuesample) from the patient prior to administration of the compound or acertain number of doses of the compound, or a certain earlier date, and(ii) no change or no substantial change in the amount of mRNA that istranscribed from the SMN1 and/or SMN2 gene and does not include exon 7of SMN1 and/or SMN2 in the patient sample relative to the amount of mRNAthat is transcribed from the SMN1 and/or SMN2 gene and does not includeexon 7 of SMN1 and/or SMN2 in an analogous sample (e.g., the same typeof tissue sample) from the patient prior to administration of thecompound or a certain number of doses of the compound, or a certainearlier date, indicate that the patient is not responsive to thecompound and that the compound is not beneficial and/or of therapeuticvalue to the patient. In certain embodiments, the patient's response ismonitored 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 16 hours, 20hours, 1 day, 2 days, 3 days, 4 days, 5 days, 7 days, 14 days, 28 days,1 month, 2 months, 3 months, 6 months, 9 months, 12 months or more afteradministration of a compound, such as a compound of Formula (I) or aform thereof as described herein. In some embodiments, the patient'sresponse is monitored after the patient has received 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25or more doses of a compound, such as a compound of Formula (I) or a formthereof as described herein. In some embodiments, the patient's responseis monitored after the administration of 1-5, 5-10, 10-15, 15-20, 20-30,30-40, 40-50, or 50-100 doses of a compound, such as a compound ofFormula (I) or a form thereof as described herein. In some embodiments,the patient's response is monitored over a period of days, weeks, monthsor years during or after the continuous administration of a compound,such as a compound of Formula (I) or a form thereof as described herein.

In another specific embodiment, provided herein is a method formonitoring an SMA patient's response to a compound, comprising: (a)administering a compound to an SMA patient; (b) contacting a sample(e.g., blood sample or tissue sample) obtained or derived from thepatient with a forward SMN primer described below (e.g., SEQ ID NO. 11or 13) and/or a reverse SMN primer described herein (e.g., SEQ ID NO. 9or 12) along with applicable components for, e.g., RT-PCR (e.g.,endpoint RT-PCR and/or RT-qPCR), PCR (e.g., qPCR), or rolling circleamplification; and (c) detecting the amount of mRNA that is transcribedfrom the SMN1 and/or SMN2 gene and includes exon 7 of SMN1 and/or SMN2and the amount of mRNA that is transcribed from the SMN1 and/or SMN2gene and does not include exon 7 of SMN1 and/or SMN2, wherein (1)(i) anincrease in the amount of mRNA that is transcribed from the SMN1 and/orSMN2 gene and includes exon 7 of SMN1 and/or SMN2 in the patient samplerelative to the amount of mRNA that is transcribed from the SMN1 and/orSMN2 gene and includes exon 7 of SMN1 and/or SMN2 in an analogous sample(e.g., from the same type of tissue sample) from the patient prior toadministration of the compound or a certain number of doses of thecompound, or a certain earlier date, and (ii) a decrease in the amountof mRNA that is transcribed from the SMN1 and/or SMN2 gene and does notinclude exon 7 of SMN1 and/or SMN2 in the patient sample relative to theamount of mRNA that is transcribed from the SMN1 and/or SMN2 gene anddoes not include exon 7 of SMN1 and/or SMN2 in an analogous sample(e.g., from the same type of tissue sample) from the patient prior toadministration of the compound or a certain number of doses of thecompound, or a certain earlier date, indicate that the patient isresponsive to the compound and that the compound may be or is beneficialand/or of therapeutic value to the patient; and (2)(i) no change or nosubstantial change in the amount of mRNA that is transcribed from theSMN1 and/or SMN2 gene and includes exon 7 of SMN1 and/or SMN2 in thepatient sample relative to the amount of mRNA that is transcribed fromthe SMN1 and/or SMN2 gene and includes exon 7 of SMN1 and/or SMN2 in ananalogous sample (e.g., the same type of tissue sample) from the patientprior to administration of the compound or a certain number of doses ofthe compound, or a certain earlier date, and (ii) no change or nosubstantial change in the amount of mRNA that is transcribed from theSMN1 and/or SMN2 gene and does not include exon 7 of SMN1 and/or SMN2 inthe patient sample relative to the amount of mRNA that is transcribedfrom the SMN1 and/or SMN2 gene and does not include exon 7 of SMN1and/or SMN2 in an analogous sample (e.g., the same type of tissuesample) from the patient prior to administration of the compound or acertain number of doses of the compound, or a certain earlier date,indicate that the patient is not responsive to the compound and that thecompound is not beneficial and/or of therapeutic value to the patient.In certain embodiments, the patient's response is monitored 1 hour, 2hours, 4 hours, 8 hours, 12 hours, 16 hours, 20 hours, 1 day, 2 days, 3days, 4 days, 5 days, 7 days, 14 days, 28 days, 1 month, 2 months, 3months, 6 months, 9 months, 12 months or more after administration of acompound, such as a compound of Formula (I) or a form thereof asdescribed herein. In some embodiments, the patient's response ismonitored after the patient has received 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more dosesof a compound, such as a compound of Formula (I) or a form thereof asdescribed herein. In some embodiments, the patient's response ismonitored after the administration of 1-5, 5-10, 10-15, 15-20, 20-30,30-40, 40-50, or 50-100 doses of a compound, such as a compound ofFormula (I) or a form thereof as described herein. In some embodiments,the patient's response is monitored over a period of days, weeks, monthsor years during or after the continuous administration of a compound,such as a compound of Formula (I) or a form thereof as described herein.

In a specific embodiment, provided herein is a method for monitoring anSMA patient's response to a compound, comprising: (a) contacting an SMApatient sample (e.g., blood sample or tissue sample) or a sample derivedfrom an SMA patient (e.g., a blood sample or tissue sample that has beenprocessed to extract RNA) with an SMN probe (e.g., SEQ ID NO. 10) alongwith applicable components for, e.g., RT-PCR (e.g., endpoint RT-PCRand/or RT-qPCR), PCR (e.g., qPCR) or rolling circle amplification,wherein the sample is from or derived from an SMA patient administered acompound (e.g., a compound of Formula (I) or a form thereof as describedherein); and (b) detecting the amount of mRNA that is transcribed fromthe SMN1 and/or SMN2 gene and includes exon 7 of SMN1 and/or SMN2 andthe amount of mRNA that is transcribed from the SMN1 and/or SMN2 geneand does not include exon 7 of SMN1 and/or SMN2, wherein (1)(i) anincrease in the amount of mRNA that is transcribed from the SMN1 and/orSMN2 gene and includes exon 7 of SMN1 and/or SMN2 in the patient samplerelative to the amount of mRNA that is transcribed from the SMN1 and/orSMN2 gene and includes exon 7 of S SMN1 and/or MN2 in an analogoussample (e.g., from the same type of tissue sample) from the patientprior to administration of the compound or a certain number of doses ofthe compound, or a certain earlier date, and (ii) a decrease in theamount of mRNA that is transcribed from the SMN1 and/or SMN2 gene anddoes not include exon 7 of SMN1 and/or SMN2 in the patient samplerelative to the amount of mRNA that is transcribed from the SMN1 and/orSMN2 gene and does not include exon 7 of SMN1 and/or SMN2 in ananalogous sample (e.g., from the same type of tissue sample) from thepatient prior to administration of the compound or a certain number ofdoses of the compound, or a certain earlier date, indicate that thepatient is responsive to the compound and that the compound may be or isbeneficial and/or of therapeutic value to the patient; and (2)(i) nochange or no substantial change in the amount of mRNA that istranscribed from the SMN1 and/or SMN2 gene and includes exon 7 of SMN1and/or SMN2 in the patient sample relative to the amount of mRNA that istranscribed from the SMN1 and/or SMN2 gene and includes exon 7 of SMN1and/or SMN2 in an analogous sample (e.g., the same type of tissuesample) from the patient prior to administration of the compound or acertain number of doses of the compound, or a certain earlier date, and(ii) no change or no substantial change in the amount of mRNA that istranscribed from the SMN1 and/or SMN2 gene and does not include exon 7of SMN1 and/or SMN2 in the patient sample relative to the amount of mRNAthat is transcribed from the SMN1 and/or SMN2 gene and does not includeexon 7 of SMN1 and/or SMN2 in an analogous sample (e.g., the same typeof tissue sample) from the patient prior to administration of thecompound or a certain number of doses of the compound, or a certainearlier date, indicate that the patient is not responsive to thecompound and that the compound is not beneficial and/or of therapeuticvalue to the patient. In certain embodiments, the patient's response ismonitored 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 16 hours, 20hours, 1 day, 2 days, 3 days, 4 days, 5 days, 7 days, 14 days, 28 days,1 month, 2 months, 3 months, 6 months, 9 months, 12 months or more afteradministration of a compound, such as a compound of Formula (I) or aform thereof as described herein. In some embodiments, the patient'sresponse is monitored after the patient has received 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25or more doses of a compound, such as a compound of Formula (I) or a formthereof as described herein. In some embodiments, the patient's responseis monitored after the administration of 1-5, 5-10, 10-15, 15-20, 20-30,30-40, 40-50, or 50-100 doses of a compound, such as a compound ofFormula (I) or a form thereof as described herein. In some embodiments,the patient's response is monitored over a period of days, weeks, monthsor years during or after the continuous administration of a compound,such as a compound of Formula (I) or a form thereof as described herein.

In another specific embodiment, provided herein is a method formonitoring an SMA patient's response to a compound, comprising: (a)administering a compound to an SMA patient; (b) contacting a sample(e.g., blood sample or tissue sample) obtained or derived from thepatient with an SMN probe (e.g., SEQ ID NO. 10) along with applicablecomponents for, e.g., RT-PCR (e.g., endpoint RT-PCR and/or RT-qPCR), PCR(e.g., qPCR) or rolling circle amplification; and (c) detecting theamount of mRNA that is transcribed from the SMN1 and/or SMN2 gene andincludes exon 7 of SMN1 and/or SMN2 and the amount of mRNA that istranscribed from the SMN1 and/or SMN2 gene and does not include exon 7of SMN1 and/or SMN2, wherein (1)(i) an increase in the amount of mRNAthat is transcribed from the SMN1 and/or SMN2 gene and includes exon 7of SMN1 and/or SMN2 in the patient sample relative to the amount of mRNAthat is transcribed from the SMN1 and/or SMN2 gene and includes exon 7of SMN1 and/or SMN2 in an analogous sample (e.g., from the same type oftissue sample) from the patient prior to administration of the compoundor a certain number of doses of the compound, or a certain earlier date,and (ii) a decrease in the amount of mRNA that is transcribed from theSMN1 and/or SMN2 gene and does not include exon 7 of SMN1 and/or SMN2 inthe patient sample relative to the amount of mRNA that is transcribedfrom the SMN1 and/or SMN2 gene and does not include exon 7 of SMN1and/or SMN2 in an analogous sample (e.g., from the same type of tissuesample) from the patient prior to administration of the compound or acertain number of doses of the compound, or a certain earlier date,indicate that the patient is responsive to the compound and that thecompound may be or is beneficial and/or of therapeutic value to thepatient; and (2)(i) no change or no substantial change in the amount ofmRNA that is transcribed from the SMN1 and/or SMN2 gene and includesexon 7 of SMN1 and/or SMN2 in the patient sample relative to the amountof mRNA that is transcribed from the SMN1 and/or SMN2 gene and includesexon 7 of SMN1 and/or SMN2 in an analogous sample (e.g., the same typeof tissue sample) from the patient prior to administration of thecompound or a certain number of doses of the compound, or a certainearlier date, and (ii) no change or no substantial change in the amountof mRNA that is transcribed from the SMN1 and/or SMN2 gene and does notinclude exon 7 of SMN1 and/or SMN2 in the patient sample relative to theamount of mRNA that is transcribed from the SMN1 and/or SMN2 gene anddoes not include exon 7 of SMN1 and/or SMN2 in an analogous sample(e.g., the same type of tissue sample) from the patient prior toadministration of the compound or a certain number of doses of thecompound, or a certain earlier date, indicate that the patient is notresponsive to the compound and that the compound is not beneficialand/or of therapeutic value to the patient. In certain embodiments, thepatient's response is monitored 1 hour, 2 hours, 4 hours, 8 hours, 12hours, 16 hours, 20 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 7days, 14 days, 28 days, 1 month, 2 months, 3 months, 6 months, 9 months,12 months or more after administration of a compound, such as a compoundof Formula (I) or a form thereof as described herein. In someembodiments, the patient's response is monitored after the patient hasreceived 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25 or more doses of a compound, such as acompound of Formula (I) or a form thereof as described herein. In someembodiments, the patient's response is monitored after theadministration of 1-5, 5-10, 10-15, 15-20, 20-30, 30-40, 40-50, or50-100 doses of a compound, such as a compound of Formula (I) or a formthereof as described herein. In some embodiments, the patient's responseis monitored over a period of days, weeks, months or years during orafter the continuous administration of a compound, such as a compound ofFormula (I) or a form thereof as described herein.

In a specific embodiment, provided herein is a method for monitoring anSMA patient's response to a compound, comprising: (a) contacting an SMApatient sample (e.g., blood sample or tissue sample) or a sample derivedfrom an SMA patient (e.g., a blood sample or tissue sample that has beenprocessed to extract RNA) with a forward SMN primer described below(e.g., SEQ ID NO. 11 or 13) and/or a reverse SMN primer described herein(e.g., SEQ ID NO. 9 or 12) and/or an SMN probe (SEQ ID NO. 10) alongwith applicable components for, e.g., RT-PCR (e.g., endpoint RT-PCRand/or RT-qPCR), PCR (e.g., qPCR) or rolling circle amplification,wherein the sample is from or derived from an SMA patient administered acompound (e.g., a compound of Formula (I) or a form thereof as describedherein); and (b) detecting the amount of mRNA that is transcribed fromthe SMN1 and/or SMN2 gene and includes exon 7 of SMN1 and/or SMN2 andthe amount of mRNA that is transcribed from the SMN1 and/or SMN2 geneand does not include exon 7 of SMN1 and/or SMN2, wherein (1)(i) anincrease in the amount of mRNA that is transcribed from the SMN1 and/orSMN2 gene and includes exon 7 of SMN1 and/or SMN2 in the patient samplerelative to the amount of mRNA that is transcribed from the SMN1 and/orSMN2 gene and includes exon 7 of SMN2 in an analogous sample (e.g., fromthe same type of tissue sample) from the patient prior to administrationof the compound or a certain number of doses of the compound, or acertain earlier date, and (ii) a decrease in the amount of mRNA that istranscribed from the SMN1 and/or SMN2 gene and does not include exon 7of SMN1 and/or SMN2 in the patient sample relative to the amount of mRNAthat is transcribed from the SMN1 and/or SMN2 gene and does not includeexon 7 of SMN1 and/or SMN2 in an analogous sample (e.g., from the sametype of tissue sample) from the patient prior to administration of thecompound or a certain number of doses of the compound, or a certainearlier date, indicate that the patient is responsive to the compoundand that the compound may be or is beneficial and/or of therapeuticvalue to the patient; and (2)(i) no change or no substantial change inthe amount of mRNA that is transcribed from the SMN1 and/or SMN2 geneand includes exon 7 of SMN1 and/or SMN2 in the patient sample relativeto the amount of mRNA that is transcribed from the SMN1 and/or SMN2 geneand includes exon 7 of SMN1 and/or SMN2 in an analogous sample (e.g.,the same type of tissue sample) from the patient prior to administrationof the compound or a certain number of doses of the compound, or acertain earlier date, and (ii) no change or no substantial change in theamount of mRNA that is transcribed from the SMN1 and/or SMN2 gene anddoes not include exon 7 of SMN1 and/or SMN2 in the patient samplerelative to the amount of mRNA that is transcribed from the SMN1 and/orSMN2 gene and does not include exon 7 of SMN1 and/or SMN2 in ananalogous sample (e.g., the same type of tissue sample) from the patientprior to administration of the compound or a certain number of doses ofthe compound, or a certain earlier date, indicate that the patient isnot responsive to the compound and that the compound is not beneficialand/or of therapeutic value to the patient. In certain embodiments, thepatient's response is monitored 1 hour, 2 hours, 4 hours, 8 hours, 12hours, 16 hours, 20 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 7days, 14 days, 28 days, 1 month, 2 months, 3 months, 6 months, 9 months,12 months or more after administration of a compound, such as a compoundof Formula (I) or a form thereof as described herein. In someembodiments, the patient's response is monitored after the patient hasreceived 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25 or more doses of a compound, such as acompound of Formula (I) or a form thereof as described herein. In someembodiments, the patient's response is monitored after theadministration of 1-5, 5-10, 10-15, 15-20, 20-30, 30-40, 40-50, or50-100 doses of a compound, such as a compound of Formula (I) or a formthereof as described herein. In some embodiments, the patient's responseis monitored over a period of days, weeks, months or years during orafter the continuous administration of a compound, such as a compound ofFormula (I) or a form thereof as described herein.

In another specific embodiment, provided herein is a method formonitoring an SMA patient's response to a compound, comprising: (a)administering a compound to an SMA patient; (b) contacting a sample(e.g., blood sample or tissue sample) obtained or derived from thepatient with a forward SMN primer described below (e.g., SEQ ID NO. 11or 13) and/or a reverse SMN primer described herein (e.g., SEQ ID NO. 9or 12) and/or an SMN probe (SEQ ID NO. 10) along with applicablecomponents for, e.g., RT-PCR (e.g., endpoint RT-PCR and/or RT-qPCR), PCR(e.g., qPCR) or rolling circle amplification; and (c) detecting theamount of mRNA that is transcribed from the SMN1 and/or SMN2 gene andincludes exon 7 of SMN1 and/or SMN2 and the amount of mRNA that istranscribed from the SMN1 and/or SMN2 gene and does not include exon 7of SMN1 and/or SMN2, wherein (1)(i) an increase in the amount of mRNAthat is transcribed from the SMN1 and/or SMN2 gene and includes exon 7of SMN1 and/or SMN2 in the patient sample relative to the amount of mRNAthat is transcribed from the SMN1 and/or SMN2 gene and includes exon 7of SMN1 and/or SMN2 in an analogous sample (e.g., from the same type oftissue sample) from the patient prior to administration of the compoundor a certain number of doses of the compound, or a certain earlier date,and (ii) a decrease in the amount of mRNA that is transcribed from theSMN1 and/or SMN2 gene and does not include exon 7 of SMN1 and/or SMN2 inthe patient sample relative to the amount of mRNA that is transcribedfrom the SMN1 and/or SMN2 gene and does not include exon 7 of SMN1and/or SMN2 in an analogous sample (e.g., from the same type of tissuesample) from the patient prior to administration of the compound or acertain number of doses of the compound, or a certain earlier date,indicate that the patient is responsive to the compound and that thecompound may be or is beneficial and/or of therapeutic value to thepatient; and (2)(i) no change or no substantial change in the amount ofmRNA that is transcribed from the SMN1 and/or SMN2 gene and includesexon 7 of SMN1 and/or SMN2 in the patient sample relative to the amountof mRNA that is transcribed from the SMN1 and/or SMN2 gene and includesexon 7 of SMN1 and/or SMN2 in an analogous sample (e.g., the same typeof tissue sample) from the patient prior to administration of thecompound or a certain number of doses of the compound, or a certainearlier date, and (ii) no change or no substantial change in the amountof mRNA that is transcribed from the SMN1 and/or SMN2 gene and does notinclude exon 7 of SMN1 and/or SMN2 in the patient sample relative to theamount of mRNA that is transcribed from the SMN2 gene and does notinclude exon 7 of SMN1 and/or SMN2 in an analogous sample (e.g., thesame type of tissue sample) from the patient prior to administration ofthe compound or a certain number of doses of the compound, or a certainearlier date, indicate that the patient is not responsive to thecompound and that the compound is not beneficial and/or of therapeuticvalue to the patient. In certain embodiments, the patient's response ismonitored 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 16 hours, 20hours, 1 day, 2 days, 3 days, 4 days, 5 days, 7 days, 14 days, 28 days,1 month, 2 months, 3 months, 6 months, 9 months, 12 months or more afteradministration of a compound, such as a compound of Formula (I) or aform thereof as described herein. In some embodiments, the patient'sresponse is monitored after the patient has received 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25or more doses of a compound, such as a compound of Formula (I) or a formthereof as described herein. In some embodiments, the patient's responseis monitored after the administration of 1-5, 5-10, 10-15, 15-20, 20-30,30-40, 40-50, or 50-100 doses of a compound, such as a compound ofFormula (I) or a form thereof as described herein. In some embodiments,the patient's response is monitored over a period of days, weeks, monthsor years during or after the continuous administration of a compound,such as a compound of Formula (I) or a form thereof as described herein.

In specific embodiments, SMA in a patient is caused by an inactivatingmutation or deletion in the SMN1 gene on both chromosomes, resulting ina loss of SMN1 gene function. KITS

In one aspect, provided herein are pharmaceutical or assay kitscomprising an SMN primer or probe described herein, in one or morecontainers, and instructions for use. In one embodiment, apharmaceutical or assay kit comprises, in a container, one or more SMNreverse primers (e.g., SEQ ID NO. 2, 9 and/or 12) and/or one or more SMNforward primers (SEQ ID NO. 1, 7, 8, 11 and/or 13)) and instructions foruse. In another embodiment, a pharmaceutical or assay kit comprises, inone container, an SMN reverse primer (e.g., SEQ ID NO. 2, 9 or 12), anSMN forward primer (SEQ ID NO. 1, 7, 8, 11 or 13)) and instructions foruse.

In one embodiment, a pharmaceutical or assay kit comprises, in separatecontainers, one SMN reverse primer (e.g., SEQ ID NO. 2, 9 or 12) in onecontainer, another SMN forward primer (e.g., SEQ ID NO. 1, 7, 8, 11 or13)) in another container, and instructions for use.

In certain embodiments, applicable components needed for a PCR (e.g.,qPCR), RT-PCR (e.g., endpoint RT-PCR and/or RT-qPCR) or rolling circleamplification, such as polymerase, deoxynucleoside triphosphates, etc.,are included in such kits. In some embodiments, components needed forhybridization are included in such kits. A pharmaceutical or assay kitcontaining such primers can be used in PCR and RT-PCR to, e.g.: (i)assess whether a therapeutic agent (e.g., a compound of Formula (I) or aform thereof) enhances inclusion of exon 7 of SMN1 and/or SMN2 into mRNAthat is transcribed from the SMN1 and/or SMN2 gene, (ii) monitor theamount of mRNA that is transcribed from the SMN1 and/or SMN2 gene andincludes exon 7 of SMN1 and/or SMN2 and the amount of mRNA that istranscribed from the SMN1 and/or SMN2 gene and does not include exon 7of SMN1 and/or SMN2, and/or (iii) monitor a subject's response to atherapeutic agent (e.g., a compound of Formula (I) or a form thereof).In other embodiments, the subject is a human subject. In otherembodiments, the human subject is a human patient. In certain otherembodiments, the human patient is a human SMA patient.

In a specific embodiment, a pharmaceutical or assay kit comprises theforward primer with the sequence found in SEQ ID NO. 1, in a container,and the reverse primer with the sequence found in SEQ ID NO. 2, inanother container. In certain embodiments, these primers are used inRT-PCR (e.g., endpoint RT-PCR and/or RT-qPCR), PCR (e.g., qPCR) orrolling circle amplification for amplifying nucleotide sequences encodedby a human SMN1 minigene or human SMN2 minigene, such as described thosedescribed herein or in International Publication No. WO 2009/151546 orU.S. Patent Application Publication No. 2011/0086833, each of which isincorporated herein by reference in its entirety. In other embodiments,these primers are used as probes in, e.g., hybridization assays, such asSouthern blot or Northern blot.

In a specific embodiment, a pharmaceutical or assay kit comprises theforward primer with the nucleotide sequence found in SEQ ID NO. 7, in acontainer, and the reverse primer with the nucleotide sequence found inSEQ ID NO. 9, in another container. In certain embodiments, theseprimers are used in RT-PCR (e.g., endpoint RT-PCR and/or RT-qPCR), PCR(e.g., qPCR) or rolling circle amplification for amplifying nucleotidesequences encoded by endogenous human SMN1 and SMN2 genes. In otherembodiments, these primers are used as probes in, e.g., hybridizationassays, such as Southern blot or Northern blot.

In another specific embodiment, a pharmaceutical or assay kit comprisesthe forward primer with the nucleotide sequence found in SEQ ID NO. 8,in a container, and the reverse primer with the nucleotide sequencefound in SEQ ID NO. 9, in another container. In certain embodiments,these primers are used in RT-PCR (e.g., endpoint RT-PCR and/or RT-qPCR),PCR (e.g., qPCR) or rolling circle amplification for amplifyingnucleotide sequences encoded by the endogenous human SMN2 gene. In otherembodiments, these primers are used as probes in, e.g., hybridizationassays, such as Southern blot or Northern blot.

In a specific embodiment, a pharmaceutical or assay kit comprises theforward primer with the nucleotide sequence found in SEQ ID NO. 7, in acontainer, the forward primer with the nucleotide sequence found in SEQID NO. 8, in another container, and the reverse primer with thenucleotide sequence found in SEQ ID NO. 9, in another container. Incertain embodiments, these primers are used in RT-PCR (e.g., endpointRT-PCR and/or RT-qPCR), PCR (e.g., qPCR) or rolling circle amplificationfor amplifying nucleotide sequences encoded by endogenous human SMN1 andSMN2 genes. In other embodiments, these primers are used as probes in,e.g., hybridization assays, such as Southern blot or Northern blot.

In a specific embodiment, a pharmaceutical or assay kit comprises theforward primer with the nucleotide sequence found in SEQ ID NO. 11, in acontainer, and the reverse primer with the nucleotide sequence found inSEQ ID NO. 12, in another container. In certain embodiments, theseprimers are used in RT-PCR (e.g., endpoint RT-PCR and/or RT-qPCR), PCR(e.g., qPCR) or rolling circle amplification for amplifying nucleotidesequences encoded by endogenous human SMN1 and SMN2 genes. In otherembodiments, these primers are used as probes in, e.g., hybridizationassays, such as Southern blot or Northern blot.

In a specific embodiment, a pharmaceutical or assay kit comprises theforward primer with the nucleotide sequence found in SEQ ID NO. 11, in acontainer, and the reverse primer with the nucleotide sequence found inSEQ ID NO. 9, in another container. In certain embodiments, theseprimers are used in RT-PCR (e.g., endpoint RT-PCR and/or RT-qPCR), PCR(e.g., qPCR) or rolling circle amplification for amplifying nucleotidesequences encoded by endogenous human SMN1 and SMN2 genes. In otherembodiments, these primers are used as probes in, e.g., hybridizationassays, such as Southern blot or Northern blot.

In a specific embodiment, a pharmaceutical or assay kit comprises theforward primer with the nucleotide sequence found in SEQ ID NO. 13, in acontainer, and the reverse primer with the nucleotide sequence found inSEQ ID NO. 12, in another container. In certain embodiments, theseprimers are used in RT-PCR (e.g., endpoint RT-PCR and/or RT-qPCR), PCR(e.g., qPCR) or rolling circle amplification for amplifying nucleotidesequences encoded by endogenous human SMN1 and SMN2 genes. In otherembodiments, these primers are used as probes in, e.g., hybridizationassays, such as Southern blot or Northern blot.

In a specific embodiment, a pharmaceutical or assay kit comprises theforward primer with the nucleotide sequence found in SEQ ID NO. 13, in acontainer, and the reverse primer with the nucleotide sequence found inSEQ ID NO. 9, in another container. In certain embodiments, theseprimers are used in RT-PCR (e.g., endpoint RT-PCR and/or RT-qPCR), PCR(e.g., qPCR) or rolling circle amplification for amplifying nucleotidesequences encoded by endogenous human SMN1 and SMN2 genes. In otherembodiments, these primers are used as probes in, e.g., hybridizationassays, such as Southern blot or Northern blot.

In a specific embodiment, a pharmaceutical or assay kit comprises theforward primer with the nucleotide sequence found in SEQ ID NO. 1, in acontainer, and the reverse primer with the nucleotide sequence found inSEQ ID NO. 9, in another container. In certain embodiments, theseprimers are used in RT-PCR (e.g., endpoint RT-PCR and/or RT-qPCR), PCR(e.g., qPCR) or rolling circle amplification for amplifying nucleotidesequences encoded by endogenous human SMN1 and SMN2 genes. In otherembodiments, these primers are used as probes in, e.g., hybridizationassays, such as Southern blot or Northern blot.

In a specific embodiment, a pharmaceutical or assay kit comprises theforward primer with the nucleotide sequence found in SEQ ID NO. 1, in acontainer, and the reverse primer with the nucleotide sequence found inSEQ ID NO. 12, in another container. In certain embodiments, theseprimers are used in RT-PCR (e.g., endpoint RT-PCR and/or RT-qPCR), PCR(e.g., qPCR) or rolling circle amplification for amplifying nucleotidesequences encoded by endogenous human SMN1 and SMN2 genes. In otherembodiments, these primers are used as probes in, e.g., hybridizationassays, such as Southern blot or Northern blot.

In another embodiment, a pharmaceutical or assay kit comprises an SMNprobe described herein (e.g., SEQ ID NO. 3 or 10), in one container. Inother embodiments, the probe is used in, e.g., a hybridization assay,such as a Southern blot or Northern blot. In a specific embodiment, theprobe is used in RT-qPCR or qPCR. In certain embodiments, componentsneeded for a PCR (e.g., qPCR), RT-PCR (e.g., endpoint RT-PCR and/orRT-qPCR) or rolling circle amplification, such as polymerase,deoxynucleoside triphosphates, primers, etc., are included in such kits.In some embodiments, components needed for hybridization are included insuch kits.

In one embodiment, a pharmaceutical or assay kit comprises an SMNreverse primer (e.g., SEQ ID NO. 2, 9 or 12) in one container, an SMNforward primer (e.g., SEQ ID NO. 1, 7, 8, 11 or 13) in anothercontainer, and an SMN probe (e.g., SEQ ID NO. 3 or 10) in anothercontainer, and instructions for use. In another embodiment, apharmaceutical or assay kit comprises one or more SMN reverse primers(e.g., SEQ ID NO. 2, 9 and/or 12) in one container, one or more SMNforward primers (e.g., SEQ ID NO. 1, 7, 8, 11 and/or 13) in anothercontainer, and one or more SMN probe (e.g., SEQ ID NO. 3 and/or 10) inanother container, and instructions for use.

In certain embodiments, components needed to run a PCR, RT-PCR orrolling circle amplification, such as polymerase, deoxynucleosidetriphosphates, etc., are included in such kits. A pharmaceutical orassay kit containing such probes and/or primers can be used in PCR andRT-PCR to, e.g.: (i) assess whether a therapeutic agent (e.g., acompound of Formula (I) or a form thereof) enhances inclusion of exon 7of SMN1 and/or SMN2 into mRNA that is transcribed from the SMN1 and/orSMN2 gene, (ii) monitor the amount of mRNA that is transcribed from theSMN1 and/or SMN2 gene and includes exon 7 and the amount of mRNA that istranscribed from the SMN1 and/or SMN2 gene and does not include exon 7of SMN1 and/or SMN2, and/or (iii) monitor a subject's response to atherapeutic agent (e.g., a compound of Formula (I) or a form thereof).In other embodiments, the subject is a human subject. In otherembodiments, the human subject is a human patient. In certain otherembodiments, the human patient is a human SMA patient.

In another aspect, provided herein is a pharmaceutical kit comprising acompound of Formula (I) or a form thereof, in a container, andinstructions for use of the compound or form thereof. In a specificembodiment, provided herein is a pharmaceutical kit comprising apharmaceutical composition comprising a compound of Formula (I) or aform thereof and a pharmaceutically acceptable carrier, excipient ordiluent, and instructions for use. In another specific embodiment,provided herein is a pharmaceutical kit comprising a pharmaceuticalcomposition comprising an effective amount of a compound of Formula (I)or a form thereof and a pharmaceutically acceptable carrier, excipientor diluent, and instructions for use. In one embodiment, theinstructions for use explain one, two or more of the following: thedose, route of administration, frequency of administration and sideeffects of administration of a compound of Formula (I) or a form thereofto a subject. In other embodiments, the subject is a human subject. Inother embodiments, the human subject is a human patient. In certainother embodiments, the human patient is a human SMA patient.

As disclosed herein, general methods for preparing the compounds ofFormula (I) or a form thereof as described herein are available viastandard, well-known synthetic methodology. Many of the startingmaterials are commercially available or, when not available, can beprepared using the routes described below using techniques known tothose skilled in the art. The synthetic schemes provided herein comprisemultiple reaction steps, each of which is intended to stand on its ownand can be carried out with or without any preceding or succeedingstep(s). In other words, each of the individual reaction steps of thesynthetic schemes provided herein in isolation is contemplated.

General Synthetic Methods

Compounds of Formula (I), wherein R₂ is a monocyclic or bicyclic aryl,heterocyclyl or heteroaryl ring system, may be prepared as described inScheme A below.

Methyl ketone Compound A1 is reacted with dialkyl carbonate Compound A1a(where R^(x) is C₁₋₄alkyl and the like) in the presence of a base (suchas NaH and the like) in a suitable solvent (such as THF and the like) toprovide Compound A3. Alternatively, ester Compound A2 is reacted withacetic acid ester Compound A2a (where R^(y) is C₁₋₄alkyl and the like)in the presence of a base (such as LDA and the like) in a suitablesolvent (such as THF and the like) to provide Compound A3. Compound A3is further reacted in the presence of an alcohol (such as MeOH and thelike) and an acid catalyst (such as p-TsOH and the like) to provideacetal Compound A4 (where R^(z) is C₁₋₄alkyl and the like). EitherCompound A3 or Compound A4 is reacted with Compound A5 (where Xrepresents various reactive groups, which may be used to provide aplurality of R₁ functional group substituents by reacting suitablestarting materials with Compound A5 or Compound A6 using techniquesknown to a person of ordinary skill in the art) in the presence of anacid (such as PPA, p-TsOH and the like) and a suitable solvent (such asDMA and the like) to afford Compound A6.

Compounds of Formula (I), wherein R₂ is a monocyclic or bicyclicheterocyclyl or heteroaryl ring system, may be prepared as described inScheme B below.

Compound B1 is reacted with Compound B2, an optionally substitutedheterocyclyl or heteroaryl ring system (wherein the term “Het” refers toan amidine-like moiety such as, but not limited to, 2-aminopyridine,2-aminopyrimidine, 2-aminopyrazine, 3-aminopyridazine, 2-aminothiazole,4-aminothiazole, 4-aminopyrimidine and the like), in a suitable solvent(such as MeOH and the like) to provide Compound B3. Compound B3 isreacted with acetic acid ester Compound A2a (where R^(y) is C₁₋₄alkyland the like) in the presence of a base (such as LDA and the like) in asuitable solvent (such as THF and the like) to afford Compound B4.Compound B4 is reacted with Compound A5 in the presence of an acid (suchas PPA, p-TsOH and the like) and a suitable solvent (such as DMA and thelike) to afford Compound B5.

Compounds of Formula (I), wherein R₂ is a monocyclic or bicyclicheteroaryl ring system, may be prepared as described in Scheme C below.

A 2,4-diester pyrazole Compound C1 is reacted with an ca-chloro ketoneCompound C2 in the presence of a base (such as K₂CO₃ and the like) and asuitable solvent (such as acetone and the like) to afford Compound C3.Compound C3 is treated with ammonium acetate in a suitable solvent (suchas AcOH and the like) to provide Compound C4. Compound C4 is treatedwith a chlorinating reagent (such as POCl₃ and the like) to provideCompound C5. Compound C5 is reacted with an alkyl boronic acid (where Zis B(OH)₂ and R^(z) is C₁₋₄alkyl and the like) or an alkyl boronic acidester (where Z is B₂(pin)₂ also referred to as bis(pinacolato)diboronand R^(z) is C₁₋₄alkyl and the like) in the presence of a catalyst (suchas Pd(dppf)Cl₂ and the like) and a base (such as K₂CO₃ and the like) ina suitable solvent (such as DMF and the like), undergoing Suzuki crosscoupling to give Compound C6. Compound C6 is reacted with acetic acidester Compound A2a (where R^(y) is C₁₋₄alkyl and the like) in thepresence of a base (such as LDA and the like) in a suitable solvent(such as THF and the like) to afford Compound C7. Compound C7 is reactedwith Compound A5 in the presence of an acid (such as p-TsOH, PPTs andthe like) and a suitable solvent to afford Compound C8.

Compounds of Formula (I), wherein R₂ is a monocyclic or bicyclic aryl orheteroaryl ring system, may be prepared as described in Scheme D below.

Compound A5 is reacted with malonic ester Compound D1 (where R^(w) isC₁₋₄alkyl, 2,4,6-trichlorophenyl and the like) to afford Compound D2.Compound D2 is treated with a chlorinating reagent (such as POCl₃ andthe like) to provide Compound D3. Compound D3 is reacted with an R₂substituted alkyl boronic acid (where Z is B(OH)₂) or an alkyl boronicacid ester (where Z is B₂(pin)₂), wherein R₂ is aryl or heteroaryl, inthe presence of a catalyst (such as Pd(dppf)Cl₂ and the like) and a base(such as K₂CO₃ and the like) in a suitable solvent (such as DMF and thelike), undergoing Suzuki cross coupling to give Compound A6.

Compounds of Formula (I), wherein R₂ is a monocyclic or bicyclicheteroaryl ring system, may be prepared as described in Scheme E below.

Compound E1 is reacted with Compound D3 in the presence of a catalyst(such as Pd(dppf)Cl₂ and the like) and a base (such as K₂CO₃ and thelike) in a suitable solvent (such as DMF and the like), undergoingSuzuki cross coupling to give Compound E2. Compound E2 is reacted withCompound C2 in a suitable solvent (such as DMSO and the like) to affordCompound E3.

Compounds of Formula (I), wherein R₂ is a monocyclic or bicyclicheteroaryl ring system, may be prepared as described in Scheme F below.

An optionally substituted 2-aminopyridine Compound F1 is reacted with abrominating reagent (such as Br₂ and NBS and the like) to provideCompound F2. Compound F2 is reacted with Compound C2 in a suitablesolvent (such as DMSO and the like) to afford Compound F3. Compound F3is reacted with Compound F3a in the presence of a catalyst (such asPd(dppf)Cl₂ and the like) and a base (such as KOAc and the like) in asuitable solvent (such as acetonitrile and the like) to provide CompoundF4. Compound F4 is reacted with Compound D3 in the presence of acatalyst (such as Pd(dppf)Cl₂ and the like) and a base (such as K₂CO₃and the like) in a suitable solvent (such as DMF and the like),undergoing Suzuki cross coupling to give Compound F5.

Compounds of Formula (I), wherein R₂ is a monocyclic or bicyclicheteroaryl ring system, may be prepared as described in Scheme G below.

An optionally substituted azole Compound G1 (wherein the term “Het”refers to the azole ring system optionally further containing one, twoor three additional nitrogen ring members where allowed by availablevalences) is reacted with Compound D3 in a suitable solvent (such asDMSO and the like) to provide Compound G2.

Compounds of Formula (I), wherein R₂ is a monocyclic or bicyclic aryl,heterocyclyl or heteroaryl ring system, may be prepared as described inScheme H below.

Compound H1 (where R₂ is a monocyclic or bicyclic aryl, heterocyclyl orheteroaryl ring system) is reacted with Bredereck's reagent Compound H2(or DMF-DMA and the like) to form Compound H3. Compound H3 is reactedwith Compound H4 (where X represents various reactive groups, which maybe used to provide a plurality of R₁ functional group substituents byreacting suitable starting materials with Compound H4 or Compound H5using techniques known to a person of ordinary skill in the art) toprovide Compound H115.

Compounds of Formula (I), wherein R₂ is a monocyclic or bicyclic aryl orheteroaryl ring system, may be prepared as described in Scheme I below.

Compound D3 (where X is bromo and the like) is reacted with an R₂substituted alkyl boronic acid (where Z is B(OH)₂) or an alkyl boronicacid ester (where Z is B₂(pin)₂), wherein R₂ is a monocyclic or bicyclicaryl or heteroaryl ring system and the like, in the presence of acatalyst (such as Pd(dppf)Cl₂ and the like) and a base (such as K₂CO₃and the like) in a suitable solvent (such as DMF and the like),undergoing Suzuki cross coupling to provide Compound I1. Compound II isreacted with R₁—H (wherein R₁ contains a nucleophilic amino or hydroxylgroup and the like) in a suitable solvent (such as DMSO and the like) toprovide Compound I3.

Compound I1 may also be reacted with an R₁ substituted alkyl boronicacid (where Z is B(OH)₂) or an alkyl boronic acid ester (where Z isB₂(pin)₂) in the presence of a palladium catalyst (such as Pd(dppf)Cl₂and the like) and a base (such as K₂CO₃ and the like) in a suitablesolvent (such as DMF and the like) undergoing Suzuki coupling to provideCompound I3.

Alternatively, Compound D3 (where X is bromo and the like) may bereacted with R₁—H (wherein R₁ contains a nucleophilic amino or hydroxylgroup and the like) in a suitable solvent (such as DMSO and the like) toprovide Compound I2. Compound I2 is reacted with an R₂ substituted alkylboronic acid (where Z is B(OH)₂) or an alkyl boronic acid ester (where Zis B₂(pin)₂) in the presence of a catalyst (such as Pd(dppf)Cl₂ and thelike) and a base (such as K₂CO₃ and the like) in a suitable solvent(such as DMF and the like), undergoing Suzuki cross coupling to giveCompound I3.

Compounds of Formula (I), wherein R₂ is a monocyclic or bicyclic aryl,heterocyclyl or heteroaryl ring system, may be prepared as described inScheme J below.

Compound J1 (where R₂ is a monocyclic or bicyclic aryl, heterocyclyl orheteroaryl ring system) is reacted with malonic ester Compound D1 in thepresence of a base (such as TEA or DIEA and the like), a Lewis acid(such as MgCl₂ and the like) and a suitable solvent (such as ACN and thelike) to provide Compound J2. Compound J2 is treated with a chlorinatingreagent (such as POCl₃ and the like) in the presence of a base (such asHünig's base and the like) to provide Compound J3.

Compound J3 is reacted with Compound J4 (where X represents variousreactive groups, which may be used to provide a plurality of R₁functional group substituents by reacting suitable starting materialswith Compound J4, Compound J5 or Compound J6 using techniques known to aperson of ordinary skill in the art) in the presence of a base (such asNaH and the like) and a suitable solvent (such as DMF and the like) toafford Compound J5. The carboxylic ester groups of Compound J5 may behydrolyzed and decarboxylated under acidic conditions (such as TFA andthe like) in a suitable solvent (such as water and the like) to giveCompound J6.

Compound J7 (where X represents various reactive groups, which may beused to provide a plurality of R₁ functional group substituents byreacting suitable starting materials with Compound J7, Compound J8 orCompound J4 using techniques known to a person of ordinary skill in theart) is reacted with malonic diester Compound D1 the presence of a base(such as Cs₂CO₃ and the like), a metal catalyst (such as CuI and thelike) and a ligand (such as 2-nicotinic acid and the like) in thepresence of a suitable solvent (such as 1,4-dioxane and the like) toafford the diester Compound J8. The carboxylic ester groups of CompoundJ8 may be hydrolyzed using a base (such as NaOH and the like) in asuitable solvent system (such as MeOH and water and the like), thendecarboxylated and acidified using an acid (such as HCl and the like) ina suitable solvent (such as water and the like) to give Compound J4.

SPECIFIC SYNTHETIC EXAMPLES

To describe in more detail and assist in understanding, the followingnon-limiting examples are offered to more fully illustrate the scope ofcompounds described herein and are not to be construed as specificallylimiting the scope thereof. Such variations of the compounds describedherein that may be now known or later developed, which would be withinthe purview of one skilled in the art to ascertain, are considered tofall within the scope of the compounds as described herein andhereinafter claimed. These examples illustrate the preparation ofcertain compounds. Those of skill in the art will understand that thetechniques described in these examples represent techniques, asdescribed by those of ordinary skill in the art, that function well insynthetic practice, and as such constitute preferred modes for thepractice thereof. However, it should be appreciated that those of skillin the art should, in light of the present disclosure, appreciate thatmany changes can be made in the specific methods that are disclosed andstill obtain a like or similar result without departing from the spiritand scope of the present description.

Other than in the following examples of the embodied compounds, unlessindicated to the contrary, all numbers expressing quantities ofingredients, reaction conditions, experimental data, and so forth usedin the specification and claims are to be understood as being modifiedby the term “about”. Accordingly, all such numbers representapproximations that may vary depending upon the desired propertiessought to be obtained by a reaction or as a result of variableexperimental conditions. Therefore, within an expected range ofexperimental reproducibility, the term “about” in the context of theresulting data, refers to a range for data provided that may varyaccording to a standard deviation from the mean. As well, forexperimental results provided, the resulting data may be rounded up ordown to present data consistently, without loss of significant figures.At the very least, and not as an attempt to limit the application of thedoctrine of equivalents to the scope of the claims, each numericalparameter should be construed in light of the number of significantdigits and rounding techniques used by those of skill in the art.

While the numerical ranges and parameters setting forth the broad scopeof the present description are approximations, the numerical values setforth in the examples set forth below are reported as precisely aspossible. Any numerical value, however, inherently contains certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements.

Compound Examples

As used above, and throughout the present description, the followingabbreviations, unless otherwise indicated, shall be understood to havethe following meanings:

Abbreviation Meaning Δ heating (chemistry) or deletion (biology) AcOH orHOAc acetic acid Ac₂O acetic anhydride Ar argon ACN acetonitrile BINAP2,2′-bis(diphenylphosphino)-1,1′-binaphthalene B(OiPr)₃ triisopropylborate Boc tert-butoxy-carbonyl Boc₂O di-tert-butyl dicarbonate BuOHn-butanol ° C. degrees Centigrade CDI 1,1-carbonyldiimidazole orN,N′-carbonyldiimidazole (CHO)_(n) or (HCHO)_(n) paraformaldehyded/h/hr/hrs/min/s day(d)/hour(h, hr or hrs)/minute(min)/second(s)DavePhos 2-dicyclohexylphosphino-2′-(N,N- dimethylamino)biphenyl DCE1,2-dichloroethane DCM dichloromethane (CH₂Cl₂) DIAD diisopropylazodicarboxylate DIEA or DIPEA N,N-diisopropylethylamine DMAdimethylacetamide DMAP 4-(dimethylamino)pyridine DME 1,2-dimethoxyethaneDMF dimethylformamide DMSO dimethylsulfoxide EDC or EDCIN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride EtOAc ethylacetate EtOH ethanol Et₂O diethyl ether HCOH formaldehyde iPrIiodopropane JohnPhos (2-biphenyl)-di-t-butylphosphine KOAc potassiumacetate LAH lithium aluminum hydride LC/MS, LCMS or LC-MS liquidchromatographic mass spectroscopy LDA lithium diisopropylamine LiHMDS orLHMDS lithium bis(trimethylsilyl)amide MeOH methanol MeI iodomethaneMe-THF 2-methyltetrahydrofuran Me₂Zn dimethylzinc MnO₂ manganese dioxideMS mass spectroscopy NaH sodium hydride NaHS sodium hydrosulfide NaHMDSsodium bis(trimethylsilyl)amide or sodium hexamethyldisilazide NaIsodium iodide NaOAc sodium acetate NaOMe sodium methoxide NBSN-bromosuccinimide NMP N-methylpyrrolidone NMR nuclear magneticresonance o/n overnight Pd palladium Pd/C palladium on carbon Pd(dba)₂bis(dibenzylideneacetone)palladium Pd₂(dba)₃ or Pd₂dba₃tris(dibenzylideneacetone)dipalladium(0) PdCl₂(PhCN)₂trans-bis(benzonitrile)dichloropalladium(II) PdCl₂(dppf), PdCl₂dppf or[1,1′- Pd(dppf)Cl₂ bis(diphenylphosphino)ferrocene]dichloropalladium(II)Pd(OAc)₂ palladium(II) acetate Pd(PPh₃)₄ or Pd(Ph₃P)₄tetrakis(triphenylphosphine)palladium(0) Pd(PPh₃)₂Cl₂, PdCl₂(PPh₃)₂ orbis(triphenylphosphine)palladium(II) dichloride PdCl₂(Ph₃P)₂ PHBu₃BF₄ ortBu₃PHBF₄ tri-tert-butylphosphonium tetrafluoroborate PhI iodobenzenePhI(OTFA)₂ [bis(trifluoroacetoxy)iodo]benzene PhMe toluene Ph-NTf2 orPhNTf₂ N-phenyl triflimide, also referred to as N-phenyl-bis(trifluoromethanesulfonimide) POCl₃ phosphoryl chloride PPh₃triphenylphosphine PPA polyphosphoric acid PPTs pyridiniump-toluenesulfonate Psi pounds per square inch pressure PyBOP(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate rtroom temperature S-Phos, SPhos or Sphos2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl T₃P propylphosphonicanhydride TEA, Et₃N or NEt₃ triethylamine Tf₂O triflic anhydride TFAtrifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatographyTMS trimethylsilane TMSCl trimethylchlorosilane or trimethylsilylchloride TMSOK potassium trimethylsilanolate t-Bu tert-butyl TsOH,p-TsOH or pTSA tosylic acid or p-toluenesulfonic acid xantphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

Example 1 Preparation of Cpd 72

Step A: 3′-Fluoro-4′-methoxyacetophenone (336 mg, 2 mmol) was dissolvedin THF (4 mL). To the solution was added dimethyl carbonate (0.42 mL, 5mmol) and sodium hydride (200 mg, 5 mmol, 60% dispersion in mineral oil)sequentially. The mixture was heated to 60° C. for 30 minutes. Aftercooling the mixture to 0° C., the remaining sodium hydride was quenchedwith 1N aqueous HCl (20 mL). The mixture was extracted with EtOAc (20mL). The organic layer was washed with brine, dried over Na₂SO₄,filtered and concentrated. The residue was eluted from silica gel withEtOAc (25%) in hexanes, affording methyl3-(3-fluoro-4-methoxyphenyl)-3-oxopropanoate as a pale yellow oil (405mg, 89%). MS m/z 227.2 [M+H]⁺; ¹H NMR (CDCl₃, 500 MHz): δ 7.76 (1H, dd,J=8.6 Hz, 2.1 Hz), 7.72 (1H, dd, J=11.7 Hz, 2.2 Hz), 7.04 (1H, t, J=8.4Hz), 3.99 (3H, s), 3.97 (2H, s), 3.78 (3H, s).

Step B: methyl 3-(3-fluoro-4-methoxyphenyl)-3-oxopropanoate (405 mg, 1.8mmol) was dissolved in methanol (1 mL). p-Toluenesulfonic acidmonohydrate (17 mg, 0.09 mmol) was added to the solution, followed bytrimethylorthoformate (0.30 mL, 2.7 mmol). The solution was stirred at60° C. for 1 hour. Volatiles were removed with a stream of nitrogenproviding crude methyl3-(3-fluoro-4-methoxyphenyl)-3,3-dimethoxypropanoate. ¹H NMR (DMSO-d₆,500 MHz): δ 7.18-7.15 (3H, m), 3.85 (3H, s), 3.38 (3H, s), 3.10 (6H, s),2.98 (2H, s).

Step C: To the crude material (1.8 mmol) from Step B was added5-fluoropyridin-2-amine (213 mg, 1.9 mmol). The mixture was heated neatto 160° C. for 1 hour to provide7-fluoro-2-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one(475 mg, 92%). MS m/z 289.2 [M+H]⁺; ¹H NMR (CDCl₃, 500 MHz): δ 8.99 (1H,m), 7.92 (1H, dd, J=12.5 Hz, 2.2 Hz), 7.90 (1H, d, 8.5 Hz), 7.88 (1H,m), 7.73 (1H, m), 7.10 (1H, t, J=8.5 Hz), 6.85 (1H, s), 3.99 (3H, s).

Step D:7-Fluoro-2-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one(200 mg, 0.7 mmol) was combined with piperazine (430 mg, 3.5 mmol) indimethylacetamide (0.5 mL). The mixture was stirred at 150° C. for 0.5hours, then chromatographed on silica gel, eluting with 0% to 8% MeOH(3% NH₃) in CH₂Cl₂. The title compound was obtained as a yellow powder(175 mg, 71%). M.P. 191-195° C.; MS m/z 355.0 [M+H]⁺; ¹H NMR (DMSO-d₆,500 MHz): δ 8.20 (1H, d, J=2.7 Hz), 8.07-8.02 (3H, m), 7.67 (1H, d,J=9.7 Hz), 7.28 (1H, t, J=8.7 Hz), 6.93 (1H, s), 3.13 (4H, m), 2.90 (3H,s), 2.88 (4H, m), 2.34 (1H, br s).

As shown in Table 1 below, additional compounds disclosed herein may beprepared according to Example 1 by substituting the appropriate startingmaterials, reagents and reaction conditions.

Example 2 Preparation of Cpd 239

Step A: A mixture of7-bromo-2-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one(250 mg, 0.72 mmol), (R)-tert-butyl3-(methylamino)pyrrolidine-1-carboxylate (180 mg, 0.90 mmol), Pd₂dba₃(61 mg, 0.065 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine(SPhos, 78 mg, 0.19 mmol), Cs₂CO₃ (500 mg, 1.53 mmol), and1,2-dimethoxyethane (DME, 2.0 mL) were stirred under an argon atmosphereat 80° C. for 18 hours. The reaction mixture was then diluted withCH₂Cl₂/MeOH (9:1) and was filtered to remove solids. The filtrate wasconcentrated under vacuum. Purification by silica gel chromatography(10% to 20% acetone in CH₂Cl₂), followed by an ether wash, yielded(R)-tert-butyl3-((2-(3-fluoro-4-methoxyphenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)(methyl)amino)pyrrolidine-1-carboxylate(132 mg, 39%) as a light tan solid. MS m/z 469.0 [M+H]⁺.

Step B: A solution of (R)-tert-butyl3-((2-(3-fluoro-4-methoxyphenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)(methyl)amino)pyrrolidine-1-carboxylate(130 mg, 0.28 mmol) in CH₂Cl₂ (2.0 mL) and TFA (500 μL) was stirred atroom temperature for 30 minutes. The mixture was poured into 1N NaOHsolution (50 mL). The product was extracted into CH₂Cl₂/EtOH (9:1). Theorganic layer was concentrated under vacuum. Purification by silica gelchromatography (CH₂Cl₂/MeOH/NH₄OH=9/1/0.1) yielded(R)-2-(3-fluoro-4-methoxyphenyl)-7-(methyl(pyrrolidin-3-yl)amino)-4H-pyrido[1,2-a]pyrimidin-4-one(82 mg, 79%) as a yellow solid. MS m/z 369.1 [M+H]⁺.

Step C: A mixture of(R)-2-(3-fluoro-4-methoxyphenyl)-7-(methyl(pyrrolidin-3-yl)amino)-4H-pyrido[1,2-a]pyrimidin-4-one(45 mg, 0.12 mmol), DCE (500 μL), formaldehyde (37% w/w in H₂O, 200 μL),and NaBH(OAc)₃ (85 mg, 0.40 mmol) was stirred at room temperature for 15minutes. The reaction mixture was added to an aqueous K₂CO₃ solution,and the title product was extracted into CH₂Cl₂. The organic layer wasconcentrated under vacuum. Purification by silica gel chromatography(10% MeOH in CH₂Cl₂) yielded the title compound (39 mg, 85%) as anoff-white solid. M.P. 143-149° C.; MS m/z 383.5 [M+H]⁺; ¹H NMR (500 MHz,DMSO-d₆): δ 8.13 (d, 1H, J=3 Hz), 8.0-8.1 (m, 3H), 7.69 (d, 1H, J=10Hz), 7.29 (t, 1H, J=9.0 Hz), 6.90 (s, 1H), 4.58 (m, 1H), 3.92 (s, 3H),2.93 (3H, s), 2.81 (m, 1H), 2.75 (m, 1H), 2.49 (m, 1H, obscured byDMSO-d₆), 2.20 (m, 2H), 2.28 (s, 3H), 1.76 (m, 1H).

As shown in Table 1 below, additional compounds disclosed herein may beprepared according to Example 2 by substituting the appropriate startingmaterials, reagents and reaction conditions.

Example 3 Preparation of Cpd 6

Step A: A mixture of ethyl 3-(3,4-dimethoxyphenyl)-3-oxopropanoate (2.02g, 8.0 mmol), 2-amino-5-fluoropyridine (0.897 g, 8.0 mmol) and p-TsOH(152 mg, 0.8 mmol) was heated at 150° C. The mixture was melted and thensolidified. After 1 hour, the mixture was cooled to room temperature andwashed with MeCN to give2-(3,4-dimethoxyphenyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one as ayellow solid (1.356 g, 56%). MS m/z 367.5 [M+H]⁺; ¹H NMR (500 MHz,DMSO-d₆): δ 8.92 (1H, dd, J=2.9 Hz, 4.8 Hz), 8.11-8.07 (1H, m),7.85-7.82 (1H, m), 7.77 (1H, d, J=2.1 Hz), 7.09 (1H, d, J=8.6 Hz), 7.06(1H, s), 6.93 (1H, s), 3.88 (3H, s), 3.84 (3H, s),

Step B: A mixture of2-(3,4-dimethoxyphenyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one (1.50g, 5.0 mmol), piperazine (1.29 g, 15 mmol) and DIEA (1.3 mL, 7.5 mmol)in DMSO (10 mL) was heated at 120° C. After 15 hours, the volatiles wereremoved and the residue was washed with MeCN to give the title compoundas a yellow solid (1.674 g, 91%).

M.P. 182-184° C.; MS m/z 367.5 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆): δ 8.20(1H, d, J=2.7 Hz), 8.04 (1H, dd, J=2.8 Hz, 9.8 Hz), 7.79 (1H, dd, J=2.1Hz, 8.5 Hz), 7.74 (1H, d, J=2.1 Hz), 7.67 (1H, d, J=9.7 Hz), 7.07 (1H,d, J=8.5 Hz), 6.93 (1H, s), 3.87 (3H, s), 3.83 (3H, s), 3.12 (4H, m),2.88 (4H, m).

As shown in Table 1 below, additional compounds disclosed herein may beprepared according to Example 3 by substituting the appropriate startingmaterials, reagents and reaction conditions.

Example 4 Preparation of Cpd 1

Step A: A mixture of ethyl 3-(3-methoxyphenyl)-3-oxopropanoate (2.68 mL,14.0 mmol) and 2-amino-5-fluoropyridine (1.12 g, 10.0 mmol) in PPA (˜5g) was heated at 120° C. After 0.5 hours, the dark purple mixture wascooled to room temperature and treated with ice-water. The precipitatewas filtered, washed with water and MeCN to give2-(4-methoxyphenyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one as aslightly yellow solid (1.758 g, 65%). MS m/z 271.2 [M+H]⁺.

Step B: Following the procedure in Example 3, Step B,7-fluoro-2-(4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one (81 mg, 0.3mmol) and piperazine (129 mg, 1.5 mmol) in DMSO (1 mL) gave the titlecompound as a yellow solid (66 mg, 66%). M.P. 182-184° C.; MS m/z 337.3[M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆): δ 8.20 (1H, d, J=2.6 Hz), 8.16 (2H,dd, J=2.0 Hz, 7.0 Hz), 8.05 (1H, dd, J=2.7 Hz, 9.7 Hz), 7.67 (1H, d,J=9.7 Hz), 7.05 (2H, d, J=1.9 Hz, 7.0 Hz), 6.86 (1H, s), 3.83 (3H, s),3.12 (4H, m), 2.87 (4H, m).

As shown in Table 1 below, additional compounds disclosed herein may beprepared according to Example 4 by substituting the appropriate startingmaterials, reagents and reaction conditions.

Example 5 Preparation of Cpd 81 and Cpd 82

Step A: To a solution of 4-methoxy-3-(trifluoromethoxy)benzaldehyde (1.0g, 4.5 mmol) in acetone (30 mL) was added Jone's reagent (5 mL). Afterstirring at room temperature for 15 hours, methanol (2 mL) was added andthe mixture was filtered. The filtrate was concentrated, dissolved inEtOAc and washed with water. The organics were dried and concentrated togive 4-methoxy-3-(trifluoromethoxy)-benzoic acid as a white solid (1.02g, 96%), MS m/z 235.2 [M−H]⁻.

Step B: To a solution of 4-methoxy-3-(trifluoromethoxy)benzoic acid(1.02 g, 4.32 mmol) in DCM (10 mL) was added oxalyl chloride (5 mL).After refluxing for 6 hours, the solution was concentrated to give4-methoxy-3-(trifluoromethoxy)-benzoyl chloride. The crude acid chloridewas dissolved in DCM (10 mL) and cooled to 0° C. Diisopropylethylamine(1.56 mL, 9.0 mmol) and N,O-dimethylhydroxylamine (0.658 g, 6.7 mmol)were added. After stirring at room temperature for 2 hours, the mixturewas washed with water. The organics were dried, concentrated andchromatographed (5% EtOAc in CH₂Cl₂) to give4-dimethoxy-N-methyl-3-(trifluoromethoxy)benzamide as an amber oil (0.58g, 48%).

Step C: To a solution of4-dimethoxy-N-methyl-3-(trifluoromethoxy)-benzamide (0.58 g, 2.08 mmol)in THF (8 mL) at 0° C. was added MeMgBr (3.0 M, 0.83 mL, 2.5 mmol).After stirring at room temperature for 15 hours, the solution was washedwith water. The organics were dried and concentrated to give11-(4-methoxy-3-(trifluoromethoxy)phenyl)ethanone as a white solid (0.45g, 96%).

Step D: To a solution of the crude1-(2-fluoro-4,5-dimethoxyphenyl)-ethanone (0.45 g, 2.0 mmol) anddimethyl carbonate (1.5 mL, 18.2 mmol) in THF (8 mL) at room temperaturewas added NaH (60%, 0.44 g, 10.9 mmol). After heating at 75° C. for 20minutes, the mixture was quenched with NH₄Cl (satd.). The pH of themixture was adjusted to neutral with 1N HCl. The mixture was extractedwith EtOAc. The organics were dried and concentrated to give methyl3-(4-methoxy-3-(trifluoromethoxy)phenyl)-3-oxopropanoate. MS m/z 299.1[M+H]⁺. The crude product was used directly in the next step.

Step E: A solution of the crude methyl3-(4-methoxy-3-(trifluoromethoxy)phenyl)-3-oxopropanoate (2 mmol) fromstep D, p-TsOH (38 mg, 0.2 mmol) and trimethoxymethane in MeOH (4 mL)was heated at 60° C. After 1 hour, the volatiles were removed and2-amino-5-fluoropyridine (0.224 g, 2.0 mmol) was added. The mixture washeated at 150° C. for 1 hour, cooled to room temperature and washed withMeCN to give7-fluoro-2-(4-methoxy-3-(trifluoromethoxy)phenyl)-4H-pyrido[1,2-a]pyrimidin-4-one(146 mg, 21%). MS m/z 355.1 [M+H]⁺.

Step F: A mixture of7-fluoro-2-(4-methoxy-3-(trifluoromethoxy)phenyl)-4H-pyrido[1,2-a]pyrimidin-4-one(71 mg, 0.2 mmol), piperazine (38 mg, 0.4 mmol) anddiisopropylethylamine (69 uL, 0.4 mmol) in DMSO (0.5 mL) was heated at120° C. After 15 hours, the volatiles were removed and the residue waschromatographed (20% MeOH in DCM) to give two products:

Cpd 81 (8 mg, 9%) was obtained as a yellow solid. M.P. 158-162° C.; MSm/z 421.1 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆): δ 8.26 (1H, d, J=2.6 Hz),8.24 (1H, dd, J=2.2 Hz, 8.8 Hz), 8.19 (1H, m), 8.08 (1H, dd, J=2.8 Hz,9.7 Hz), 7.75 (1H, d, J=9.7 Hz), 7.37 (1H, d, J=8.8 Hz), 6.99 (1H, s),3.94 (3H, s), 3.07 (4H, m), 2.50 (4H, m, obscured by DMSO-d₆; and,

Cpd 82 (9 mg, 11%) was obtained as a yellow solid. M.P. 245-248° C.; MSm/z 407.2 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆): δ 8.21 (1H, d, J=2.7 Hz),8.11 (1H, m), 8.07-8.03 (2H, m), 7.68 (1H, d, J=9.7 Hz), 7.11 (1H, d,J=8.6 Hz), 6.87 (1H, s), 3.14 (4H, m), 2.88 (4H, m).

As shown in Table 1 below, additional compounds disclosed herein may beprepared according to Example 5 by substituting the appropriate startingmaterials, reagents and reaction conditions.

Example 6 Preparation of Cpd 70

To a suspension of2-(3,4-dimethoxyphenyl)-9-fluoro-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one(38 mg, 0.1 mmol, prepared by following the procedures in Example 3,Steps A and B in MeOH (0.5 mL) was added NaOMe (0.5 M in MeOH, 1 mL, 0.5mmol). After heating at 80° C. for 15 hours, the volatiles were removedand the residue was chromatographed (10-15% MeOH/CH₂Cl₂) to give thetitle compound as a yellow solid (18 mg, 45%). M.P. 185-187° C.; MS m/z397.3 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆): δ 8.20 (1H, d, J=2.5 Hz), 7.80(2H, m), 7.08 (1H, d, J=9.0 Hz), 7.00 (1H, s), 6.97 (1H, d, J=2.5 Hz),3.89 (3H, s), 3.87 (3H, s), 3.83 (3H, s), 3.30 (4H, m), 2.98 (4H, m).

Example 7 Preparation of Cpd 74

Step A: To a solution of 2-amino-5-methylpyrazine (1.09 g, 10 mmol) inDME (10 mL) was added ethyl 3-bromo-2-oxopropanoate (1.57 mL, 12.5mmol). The mixture was stirred at room temperature for 45 minutes. Theprecipitate was filtered, washed with Et₂O and dried to give a yellowsolid. The solid was suspended in EtOH (20 mL) and heated at 90° C.After 1.5 hours, the resulting brown solution was concentrated andadjusted to pH 7. The mixture was extracted with EtOAc. The organicswere concentrated and the residue was triturated and washed with MeCN togive ethyl 6-methylimidazo[1,2-a]pyrazine-2-carboxylate as a brown solid(0.993 g, 48%). MS m/z 206.2 [M+H]⁺.

Step B: To a solution of ethyl6-methylimidazo[1,2-a]pyrazine-2-carboxylate (0.971 g, 4.73 mmol) andEtOAc (0.98 mL, 10 mmol) in toluene (2 mL) and Me-THF (8 mL) at roomtemperature was added NaH (60%, 0.503 mg, 12.6 mmol). After heating at70° C. for 30 minutes, the mixture was cooled to room temperature,quenched with ice, adjusted to pH 7 with 1N HCl and extracted withEtOAc. The organics were combined, dried, concentrated andchromatographed to give ethyl3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-3-oxopropanoate as a brownish oil(0.93 g, 78%).

Step C: Following the procedure in Example 1 Step B, ethyl3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-3-oxopropanoate (0.913 g, 3.7mmol), p-toluenesulfonic acid monohydrate (70 mg, 0.37 mmol) andtrimethylorthoformate (0.81 mL, 7.4 mmol) in MeOH (10 mL) afforded theketal which was used directly in the next step.

Step D: Following the procedure in Example 1 Step C, the crudedimethoxypropanoate (from Step C and 2-amino-5-fluoro-pyridine (0.422 g,3.7 mmol) gave7-fluoro-2-(6-methylimidazo[1,2-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-oneas a brownish solid (0.344 g, 31%). MS m/z 295.9 [M+H]⁺; ¹H NMR (500MHz, DMSO-d₆): δ 9.09 (1H, s), 8.97-8.96 (1H, m), 8.67 (1H, s), 8.47(1H, s), 8.15-8.11 (1H, m), 7.85-7.82 (1H, m), 7.08 (1H, s), 2.42 (3H,S).

Step E: Following the procedure in Example 3, Step B,7-fluoro-2-(6-methylimidazo[1,2-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one(59 mg, 0.2 mmol) and piperazine (52 mg, 0.6 mmol) in DMSO (0.5 mL) gavethe title compound as a yellow solid (28 mg, 39%). M.P. 221-225° C.; MSm/z 362.2 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆): δ 9.07 (1H, s), 8.62 (1H,s), 8.46 (1H, s), 8.25 (1H, d, J=2.6 Hz), 8.09 (1H, d, J=2.7 Hz, 9.7Hz), 7.67 (1H, d, J=9.7 Hz), 7.00 (1H, s), 3.16 (4H, m), 2.90 (4H, m),2.44 (3H, s).

As shown in Table 1 below, additional compounds disclosed herein may beprepared according to Example 7 by substituting the appropriate startingmaterials, reagents and reaction conditions.

Example 8 Preparation of Cpd 29

Step A: Following the procedure in Example 7, Step A,2-amino-5-methylpyridine (5.41 g, 50 mmol) and ethyl3-bromo-2-oxopropanoate (7.0 mL, 50 mmol) in MeOH (50 mL) gave ethyl6-methylimidazo[1,2-a]pyridine-2-carboxylate as a yellowish solid (9.50g, 93%), MS m/z 205.1 [M+H]⁺.

Step B: Following the procedure in Example 7, Step B, ethyl6-methylimidazo[1,2-a]pyridine-2-carboxylate (0.55 g, 2.5 mmol), EtOAc(0.29 mL, 5.0 mmol) and NaH (60%, 0.20 g, 5 mmol) in toluene (5 mL) gaveethyl 3-(6-methylimidazo[1,2-a]pyridin-2-yl)-3-oxopropanoate as a yellowsolid (0.62 g, 100%), MS m/z 243.1 [M+H]⁺.

Step C: Following the procedure in Example 4, Step A, ethyl3-(6-methylimidazo[1,2-a]pyridin-2-yl)-3-oxopropanoate (246 mg, 1.0mmol) and 2-amino-5-fluoropyridine (334 mg, 1.2 mmol) in PPA (˜5 g) gave7-fluoro-2-(6-methylimidazo[1,2-a]pyridin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-oneas a yellow solid (17 mg, 6%), MS m/z 295.2 [M+H]⁺.

Step D: Following the procedure in Example 3, Step B,7-fluoro-2-(6-methylimidazo[1,2-a]pyridin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one(17 mg, 0.06 mmol) and piperazine (30 mg, 0.3 mmol) in DMSO (10 mL) gavethe title compound as a light brown solid (19 mg, 83%). M.P. 193-198°C.; MS m/z 361.3 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆): δ 8.48 (1H, s), 8.41(1H, s), 8.25 (1H, d, J=2.6 Hz), 8.06 (1H, dd, J=2.7 Hz, 9.7 Hz), 7.66(1H, d, J=9.7 Hz), 7.55 (1H, d, 9.3 Hz), 7.18 (1H, d, J=9.3 Hz), 6.96(1H, s), 3.23 (4H, m), 3.01 (4H, m), 2.29 (3H, s).

Example 9 Preparation of Cpd 170

Step A: To a solution of diethyl 1H-pyrazole-3,5-dicarboxylate (10.0 g,47 mmol) and chloroacetone (3.76 mL, 47 mmol) in acetone (200 mL) wasadded potassium carbonate (7.2 g, 52 mmol). After heating at 30° C. for6 hours, the mixture was concentrated to remove the volatiles. Theresidue was taken into EtOAc and washed with water. The organics weredried over MgSO₄ and concentrated to give diethyl1-(2-oxopropyl)-1H-pyrazole-3,5-dicarboxylate as a light brown solid,which was used directly in the next step, MS m/z 269.1 [M+H]⁺.

Step B: To a solution of diethyl 1-(2-oxopropyl)-1H-pyrazole-3,5-dicarboxylate (˜47 mmol) in acetic acid (300 mL) was added ammoniumacetate (72 g, 940 mmol). After refluxing for 48 hours, the mixture wasconcentrated to minimum volume and diluted with water. The precipitatewas filtered, washed with water and MeCN to give ethyl4-hydroxy-6-methylpyrazolo[1,5-a]pyrazine-2-carboxylate as a tan solid(6.7 g, 64%), MS m/z 222.1 [M+H]⁺.

Step C: A mixture of ethyl4-hydroxy-6-methylpyrazolo[1,5-a]pyrazine-2-carboxylate (7.18 g, 32.5mmol) in POCl₃ (80 mL) was refluxed for 15 hours. The dark mixture wasconcentrated and washed with MeCN to give ethyl4-chloro-6-methylpyrazolo[1,5-a]pyrazine-2-carboxylate (5.197 g) as anoff-white solid. The filtrate was concentrated and chromatographed togive an additional 1.42 g product (6.617 g, 85%) MS m/z 240.1 [M+H]⁺,242.1 [M+2+H]⁺.

Step D: A mixture of ethyl4-chloro-6-methylpyrazolo[1,5-a]pyrazine-2-carboxylate (5.197 g, 21.7mmol), MeB(OH)₂ (3.90 g, 65.1 mmol), K₂CO₃ (14.8 g, 107.5 mmol) andPd(PPh₃)₂Cl₂ in (456 mg, 0.65 mmol) DMF (100 mL) was degassed and heatedunder N₂ for 15 hours. The mixture was concentrated on a rotovap toremove most of the DMF and washed with water. The residue waschromatographed (2% to 5% MeOH in CH₂Cl₂) to give ethyl4,6-dimethylpyrazolo[1,5-a]pyrazine-2-carboxylate as a yellow solid(3.90 g, 82%), MS m/z 220.1 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆): δ 8.54(1H, s), 7.49 (1H, s), 4.36 (2H, q, J=7.2 Hz), 2.70 (3H, s), 2.42 (3H,s), 1.34 (3H, t, J=7.2 Hz).

Step E: To a solution of t-butyl acetate (1.63 mL, 12.1 mmol) in THF (50mL) at −78° C. was added LDA (1.5 M, 0.97 mL, 14.5 mmol). After 0.5hours, the solution was cannulated to a solution of ethyl4,6-dimethylpyrazolo[1,5-a]pyrazine-2-carboxylate (1.33 g, 6.07 mmol) inTHF (100 mL) at −30° C. After 1 hour, the mixture was quenched withsaturated NH₄Cl, adjusted to pH 5-6 and extracted with EtOAc. Thecombined organics were dried and concentrated. The residue waschromatographed (2% to 4% MeOH/CH₂Cl₂) to give t-butyl3-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-3-oxopropanoate as a yellowoil (1.696 g, 97%), MS m/z 290.2 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆): δ8.57 (1H, s), 7.50 (1H, s), 4.02 (2H, s), 2.70 (3H, s), 2.43 (3H, s),1.38 (9H, s).

Step F: A solution of t-butyl3-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-3-oxopropanoate (4.86 g,16.8 mmol) in EtOH (30 mmol) was heated at 120° C. in a capped tube.After 1 hour, the solution was cooled to room temperature and thevolatiles were removed to give ethyl3-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-3-oxopropanoate as a yellowsolid (4.44 g, 98%), MS m/z 262.2 [M+H]⁺.

Step G: A mixture of 2-amino-5-fluoro-pyridine (134 mg, 1.2 mmol), ethyl3-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-3-oxopropanoate (261 mg, 1.0mmol) and PPTs (12.6 mg, 0.05 mmol) was heated at 130° C. After 8 hours,the mixture was cooled to room temperature and chromatographed to give2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-oneas a yellow solid (220 mg, 71%). MS m/z 310.2 [M+H]⁺; ¹H NMR (500 MHz,DMSO-d₆): δ 8.97-8.95 (1H, m), 8.55 (1H, s), 8.16-8.12 (1H, m),7.87-7.85 (1H, m), 7.56 (1H, s), 7.03 (1H, s), 2.73, (3H, s), 2.43 (3H,s).

Step H: Following the procedure in Example 3, Step B,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one(309 mg, 1.0 mmol) and piperazine (1.1 mL, 10 mmol) in DMA (1.0 mL) gavethe title compound as a yellow solid (313 mg, 80%). M.P. 254-256° C.; MSm/z 390.4 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆): δ 8.55 (1H, s), 8.27 (1H,d, J=2.7 Hz), 8.12 (1H, dd, J=2.8 Hz, 9.7 Hz), 7.71 (1H, d, J=9.7 Hz),7.54 (1H, s), 6.95 (1H, s), 3.25 (4H, m), 2.72 (3H, s), 2.51 (4H, m,obscured by DMSO-d₆), 2.43 (3H, s), 2.25 (3H, s).

As shown in Table 1 below, additional compounds disclosed herein may beprepared according to Example 9 by substituting the appropriate startingmaterials, reagents and reaction conditions.

Example 10 Preparation of Cpd 163

Step A: Following the procedure in Example 5, Step E,2-acetyl-4-methylthiazole (706 mg, 5 mmol), dimethyl carbonate (15 mL,178 mmol) and NaH (60% dispersion in mineral oil, 1.14 g, 28.5 mmol)provided methyl 3-(4-methylthiazol-2-yl)-3-oxopropanoate. The crudeproduct was used directly in the next step. MS m/z 200.1 [M+H]⁺.

Step B: Following the procedure in Example 1, Step B,3-(4-methylthiazol-2-yl)-3-oxopropanoate (199 mg, 1.0 mmo),trimethylorthoformate (0.25 mL, 2.25 mmol) and toluenesulfonic acidmonohydrate (14.3 mg, 0.075 mmol) in MeOH (1.5 mL) afforded thedimethoxypropanoate.

Step C: Following the procedure in Example 1, Step C thedimethoxypropanoate from Step B and 2-amino-4-fluoro-pyridine (201.8 mg,1.8 mmol) in DMA (1.5 mL) provided7-fluoro-2-(4-methylthiazol-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (175.5mg, 67%). MS m/z 262.1 [M+H]⁺.

Step D: Following the procedure in Example 3, Step B,7-fluoro-2-(4-methylthiazol-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (52.2mg, 0.2 mmol) and piperazine (86 mg, 1 mmol) in DMSO (0.8 mL) providedthe title compound (20 mg, 30%). M.P. 142-147° C.; MS m/z 328.2 [M+H]⁺;¹H NMR (500 MHz, DMSO-d₆): δ 8.27 (1H, dd, J=2.7 Hz, 18.6 Hz), 8.11-8.16(1H, m), 7.73 (1H, t, J=9.2 Hz), 7.56 (1H, s), 6.88 (1H, d, J=3.2 Hz),3.29-3.31 (2H, m), 3.16-3.18 (2H, m), 2.89-2.91 (2H, m), 2.67-2.69 (2H,m), 2.47 (3H, s).

As shown in Table 1 below, additional compounds disclosed herein may beprepared according to Example 10 by substituting the appropriatestarting materials, reagents and reaction conditions.

Example 11 Preparation of Cpd 92

Step A: 5-Fluoronicotinic acid (1.0 g, 7.1 mmol) was dissolved in THF(10 mL) and cooled to 0° C. A 1.4 M solution of methylmagnesium bromidein THF:toluene (3:1) (11.2 mL, 15.6 mmol) was added drop wise to thesolution. The solution was allowed to warm to room temperature. Thesolution was stirred at room temperature for 4 hours, upon which 1Naqueous HCl (50 mL) was slowly added. The mixture was partitioned intoEtOAc (200 mL) and aqueous 1N NaOH (200 mL). The organic layer waswashed with brine, dried over Na₂SO₄, filtered and concentrated. Theresidue was chromatographed on silica, eluting with EtOAc (0% to 50%) inhexanes to afford 1-(5-fluoropyridin-3-yl)ethanone as a white powder(290 mg, 29%).

Step B: Following the procedure in Example 5, Step D, the methyl ketonefrom Step A, dimethyl carbonate (0.44 mL, 5.25 mmol) and sodium hydride(210 mg, 60% dispersion in mineral oil, 5.25 mmol) in THF (6 mL)afforded methyl 3-(5-fluoropyridin-3-yl)-3-oxopropanoate as an off whitepowder (278 mg, 67%).

Step C: Methyl 3-(5-fluoropyridin-3-yl)-3-oxopropanoate (138 mg, 0.7mmol) was combined with 5-fluoropyridin-2-amine (90 mg, 0.8 mmol) andtoluenesulfonic acid monohydrate (6 mg, 0.03 mmol) in dimethylacetamide(0.5 mL). The mixture was heated to 160° C. for 1 hour. The mixture wascooled to 120° C., before adding piperazine (300 mg, 3.5 mmol). Themixture was stirred at 120° C. for 1 hour. The mixture was loaded ontosilica in CH₂Cl₂ and eluted with 0% to 8% MeOH (3% NH₃) in CH₂Cl₂. Thetitle compound was obtained as a yellow powder (37 mg, 16%). M.P.201-208° C.; MS m/z 326.2 [M+H]⁺; ¹H NMR (DMSO-d₆, 500 MHz): δ 9.25 (1H,s), 8.70 (1H, d, J=2.8 Hz), 8.42 (1H, d, J=10.2 Hz), 8.22 (1H, d, 2.7Hz), 8.12 (1H, dd, J=9.8 Hz, 2.8 Hz), 7.74 (1H, d, J=9.7 Hz), 7.11 (1H,s), 3.16 (4H, m), 2.89 (4H, m), 2.37 (1H, br s).

As shown in Table 1 below, additional compounds disclosed herein may beprepared according to Example 11 by substituting the appropriatestarting materials, reagents and reaction conditions.

Example 12 Preparation of Cpd 98

Step A: 1H-Indole-5-carboxylic acid (1.0 g, 6.2 mmol) was combined withN,O-dimethylhydroxylamine hydrochloride (907 mg, 9.3 mmol),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.78 g,9.3 mmol) and N,N-diisopropylethylamine (3.2 mL, 18.6 mmol) in CH₂Cl₂(12 mL). After stirring for 4 hours at room temperature, the mixture waswashed with aqueous HCl (1N, 20 mL). The organic layer was dried overNa₂SO₄ and concentrated. The crude product was used directly in the nextstep.

Step B: The crude product from Step A was dissolved in THE (20 mL). A1.4 M solution of methylmagnesium bromide (11.2 mL, 15.6 mmol) inTHF:toluene (3:1), was added drop wise to the solution. The solution wasallowed to warm to room temperature. The solution was stirred at 50° C.for 1 hour, upon which 1N aqueous HCl (50 mL) was slowly added. Themixture was partitioned into EtOAc (200 mL) and aqueous 1N NaOH (200mL). The organic layer was washed with brine, dried over Na₂SO₄,filtered and concentrated. The residue was chromatographed on silica,eluting with EtOAc (0% to 50%) in hexanes to afford1-(1H-indol-5-yl)ethanone as a white powder (323 mg, 33%).

Step C: Following the procedure in Example 5, Step E, the methyl ketonefrom Step B, dimethyl carbonate (0.46 mL, 5.5 mmol) and sodium hydride(220 mg, 60% dispersion in mineral oil, 5.5 mmol) in THF (6 mL) affordedmethyl methyl 3-(1H-indol-5-yl)-3-oxopropanoate as an off white powder(120 mg, 27%). MS m/z 216.1 [M−H]⁻.

Step D: Following the procedure of Example 11, Step C, methyl3-(1H-indol-5-yl)-3-oxopropanoate (98 mg, 0.45 mmol),5-fluoropyridin-2-amine (56 mg, 0.5 mmol), toluenesulfonic acidmonohydrate (9 mg, 0.05 mmol) and piperazine (194 mg, 2.25 mmol) indimethylacetamide (0.5 mL) afforded the title compound as an off-whitepowder (40 mg, 26%).

M.P. 266-272° C. MS m/z 346.2 [M+H]⁺; ¹H NMR (DMSO-d₆, 500 MHz): δ 11.3(1H, s), 8.46 (1H, s), 8.22 (1H, d, J=2.8 Hz), 8.04 (1H, dd, J=9.7 Hz,2.8 Hz), 7.95 (1H, d, J=8.7 Hz), 7.69 (1H, d, J=9.7 Hz), 7.49 (1H, d,J=8.6 Hz), 7.42 (1H, t, J=2.7 Hz), 6.90 (1H, s), 6.57 (1H, m), 3.14 (4H,m), 2.89 (4H, m), 2.36 (1H, br s).

As shown in Table 1 below, additional compounds disclosed herein may beprepared according to Example 12 by substituting the appropriatestarting materials, reagents and reaction conditions.

Example 13 Preparation of Cpd 107

Step A: Following the procedure in Example 12, Step A,imidazo[1,2-a]pyridine-7-carboxylic acid (1.0 g, 6.2 mmol),N,O-dimethylhydroxylamine hydrochloride (907 mg, 9.3 mmol),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.78 g,9.3 mmol) and N,N-diisopropylethylamine (3.2 mL, 18.6 mmol) in CH₂Cl₂(12 mL) gave N-methoxy-N-methylimidazo[1,2-a]pyridine-7-carboxamide (505mg, 40%).

Step B: Following the procedure in Example 12, Step B, the product fromStep A (505 mg, 2.5 mmol), methylmagnesium bromide (3.6 mmol) in THF (10mL) afforded 1-(imidazo[1,2-a]pyridin-7-yl)ethanone (275 mg, 70%).

Step C: Following the procedure in Example 5, Step E, the methyl ketonefrom Step B (275 mg, 1.7 mmol), dimethyl carbonate (0.35 mL, 4.25 mmol)and sodium hydride (170 mg, 60% dispersion in mineral oil, 4.25 mmol) inTHF (5 mL) afforded methyl3-(imidazo[1,2-a]pyridin-7-yl)-3-oxopropanoate as an off-white powder(215 mg, 58%).

Step D: Following the procedure of Example 11, Step C, methyl3-(imidazo[1,2-a]pyridin-7-yl)-3-oxopropanoate (215 mg, 1.0 mmol),5-fluoropyridin-2-amine (123 mg, 1.1 mmol), toluenesulfonic acidmonohydrate (19 mg, 0.1 mmol) and piperazine (430 mg, 5 mmol) indimethylacetamide (1.0 mL) afforded the title compound as an off-whitepowder (40 mg, 12%). M.P. 258-270° C.; MS m/z 347.0 [M+H]⁺; ¹H NMR(DMSO-d₆, 500 MHz): δ 8.65 (1H, d, J=7.2 Hz), 8.46 (1H, s), 8.24 (1H, d,J=2.7 Hz), 8.11 (1H, dd, J=9.7 Hz, 2.7 Hz), 8.06 (1H, s), 7.75 (1H, d,J=9.7 Hz), 7.73 (1H, dd, J=7.2 Hz, 2.7 Hz), 7.71 (1H, s), 7.10 (1H, s),3.16 (4H, m), 2.89 (4H, m), 2.34 (1H, br s).

Example 14 Preparation of Cpd 171

Part 1, Step A: A mixture of 2-amino-5-fluoropyridine (11.20 g, 0.10mol) and dimethyl malonate (57.0 mL, 0.50 mol) was heated at 230° C. for1.5 hours. After cooling to room temperature, the precipitate wasfiltered and washed with ACN (3×) to give7-fluoro-2-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one as a dark solid (14g), which was used directly in the next step. MS m/z 181.3 [M+H]⁺.

Part 1, Step B: A dark mixture of crude7-fluoro-2-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one (14 g, ˜77 mmol) inPOCl₃ (50 mL) and DIEA (13.3 mL, 77 mmol) was heated at 110° C. for 15hours. The volatiles were removed and the dark residue was treated withice-water, washed with water (3×) and dried to give a brown solid. Thecrude brown solid was chromatographed (5% MeOH in CH₂Cl₂) to give2-chloro-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one as a yellow solid(9.84 g, 50%, 2 steps), MS m/z 199.2 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆):δ 8.99 (1H, dd, J=2.8 Hz, 4.7 Hz), 8.27-8.23 (1H, m), 7.85 (1H, dd,J=5.4 Hz, 9.8 Hz), 6.56 (1H, s).

Part 2: A mixture of 6-bromo-2-methylbenzo[d]oxazole (1.06 g, 5.0 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.40 g, 5.5mmol), KOAc (1.47 g, 15 mmol) and Pd(dppf)Cl₂.CH₂Cl₂ (122 mg, 0.15 mmol)in dioxane (8 mL) was degassed and heated under N₂ at 85° C. After 15hours, the mixture was diluted with EtOAc, filtered through celite andconcentrated. The residue was chromatographed to give2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazoleas a light orange solid (1.30 g, 100%), MS m/z 260.4 [M+H]⁺.

Part 3, Step A: A mixture of2-chloro-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one (0.436 g, 2.2 mmol),2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole(0.647 g, 2.5 mmol), Pd(dppf)Cl₂ in DCM (90 mg, 0.11 mmol), K₂CO₃ (2M,3.0 mL, 6.0 mmol), and ACN (6 mL) was degassed and then heated under N₂at 60° C. for 3.5 hours. The volatiles were removed and the residue waschromatographed (2.5% MeOH/CH₂Cl₂) to give7-fluoro-2-(2-methylbenzo[d]oxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-oneas an off-white solid (0.64 g, 98%). MS m/z 296.4 [M+H]⁺; ¹H NMR (500MHz, DMSO-d₆): δ 8.96-8.95 (1H, m), 8.51 (1H, d, J=1.6 Hz), 8.26 (1H,dd, J=8.5 Hz, 1.6 Hz), 8.16-8.12 (1H, m), 7.91-7.88 (1H, m), 7.78 (1H,d, J=8.4 Hz), 7.17 (1H, s), 2.67 (3H, s).

Part 3, Step B: A mixture of7-fluoro-2-(2-methylbenzo[d]oxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one(60 mg, 0.2 mmol) and 1-Methyl piperazine (0.11 mL, 1.0 mmol) in DMA(0.3 mL) was heated at 120° C. for 15 hours. The volatiles were removedand the residue was chromatographed to give the title compound as ayellow solid (46 mg, 61%). M.P. 178-183° C.; MS m/z 376.5 [M+H]⁺; ¹H NMR(500 MHz, DMSO-d₆): δ 8.47 (1H, d, J=1.5 Hz), 8.25 (1H, d, J=2.7 Hz),8.23 (1H, dd, J=1.6 Hz, 8.4 Hz), 8.11 (1H, dd, J=2.8 Hz, 9.7 Hz), 7.76(1H, d, J=8.6 Hz), 7.74 (1H, d, J=9.9 Hz), 7.06 (1H, s), 3.25 (4H, m),2.66 (3H, s), 2.25 (3H, s).

As shown in Table 1 below, additional compounds disclosed herein may beprepared according to Example 14 by substituting the appropriatestarting materials, reagents and reaction conditions.

Example 15 Preparation of 109

Step A: 2-Chloro-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one (990 mg, 5mmol, prepared according to the procedure in Example 14, Part 1) wascombined with 2-aminopyridine-5-boronic acid pinacol ester (1.21 g, 5.5mmol), tetrakis(triphenylphosphine) palladium(0) (281 mg, 0.25 mmol),CH₃CN (10 mL) and aqueous K₂CO₃ (1M, 10 mL). The mixture was heated to80° C. for 6 hours. The mixture was cooled to room temperature, and thenfiltered. The collected precipitate was washed with CH₃CN and driedunder vacuum, providing2-(6-aminopyridin-3-yl)-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one as ayellow powder (1.13 g, 88%). MS m/z 257.0 [M+H]⁺; ¹H NMR (DMSO-d₆, 500MHz): δ 8.90 (1H, m), 8.83 (1H, d, J=2.1 Hz), 8.17 (1H, dd, J=8.8 Hz,2.5 Hz), 8.07 (1H, m), 7.78 (1H, dd, J=9.8 Hz, 5.3 Hz), 6.87 (1H, s),6.58 (2H, s), 6.53 (1H, d, 8.9 Hz).

Step B. 2-(6-Aminopyridin-3-yl)-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one(254 mg, 1.0 mmol) was combined with chloroacetone (100 μL, 1.2 mmol) inDMSO (360 μL, 1.65 mmol). The mixture was heated to 120° C. for 30minutes. After cooling to room temperature, the mixture was partitionedin CH₂Cl₂ and saturated aqueous NaHCO₃. The organic layer wasconcentrated. The residue was eluted from silica with MeOH (0% to 6%) inCH₂Cl₂, affording7-fluoro-2-(2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-oneas a tan powder (136 mg, 46%). MS m/z 295.0 [M+H]⁺; ¹H NMR (DMSO-d₆, 500MHz): δ 9.40 (1H, s), 8.95 (1H, m), 8.14 (1H, m), 7.96 (1H, dd, J=9.5Hz, 1.9 Hz), 7.85 (2H, m), 7.54 (1H, J=9.4), 7.08 (1H, s), 2.36 (3H, s).

Step C:7-Fluoro-2-(2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one(45 mg, 0.15 mmol) was combined with piperazine (65 mg, 0.75 mmol) indimethylacetamide (0.5 mL). The mixture was heated to 150° C. for 1hour. The mixture was loaded onto silica and eluted with 0% to 8% MeOH(3% NH₃) in CH₂Cl₂ to afford the title compound as a tan powder (33 mg,61%). M.P. 259-267° C.; MS m/z 361.1 [M+H]⁺; ¹H NMR (DMSO-d₆, 500 MHz):δ 9.36 (1H, s), 8.23 (1H, d, J=2.7 Hz), 8.10 (1H, dd, J=9.7 Hz, 2.7 Hz),7.94 (1H, dd, J=9.5 Hz, 1.8 Hz), 7.82 (1H, s), 7.70 (1H, d, J=9.7 Hz),7.52 (1H, d, J=9.5 Hz), 6.96 (1H, s), 3.15 (4H, m), 2.89 (4H, m), 2.36(3H, s).

As shown in Table 1 below, additional compounds disclosed herein may beprepared according to Example 15 by substituting the appropriatestarting materials, reagents and reaction conditions.

Example 16 Preparation of Cpd 209

Step A: 3-Fluoropyridin-2-amine (5.0 g, 45 mmol) was combined withN-bromosuccinimide (8.0 g, 45 mmol) in CH₃CN (40 mL). The mixture wasstirred at room temperature for 30 minutes. Chloroacetone (4.3 mL, 54mmol) was added to the mixture. The mixture was heated to 100° C.,allowing the CH₃CN to evaporate. After 1 hour, the temperature wasraised to 120° C. for 2 hours. The mixture solidified upon cooling. Thesolid material was dissolved in H₂O (50 mL). To the aqueous solution wasadded 100 mL of saturated aqueous NaHCO₃. A precipitate formed, and wascollected by vacuum filtration. The solid material was washed with H₂Oand dried under vacuum. The material was loaded onto silica in CH₂Cl₂and eluted with EtOAc (0% to 30%) in CH₂Cl₂, providing6-bromo-8-fluoro-2-methylimidazo[1,2-a]pyridine as a tan powder (4.65 g,45%). MS m/z 229.2 [M+H]⁺, 231.2 [M+2+H]⁺; ¹H NMR (DMSO-d₆, 500 MHz): δ8.72 (1H, s), 7.79 (1H, s), 7.39 (1H, d, J=10.7 Hz), 2.35 (3H, s).

Step B: Following the procedure in Example 14, Part 2,6-Bromo-8-fluoro-2-methylimidazo[1,2-a]pyridine (912 mg, 4 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.32 g, 4.8mmol), [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (163mg, 0.2 mmol) and potassium acetate (784 mg, 8 mmol) provided8-fluoro-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine.The crude product was used directly in the next step.

Step C: Following the procedure in Example 14, Part 3, Step A, the crudeproduct of8-fluoro-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridinefrom step A and 2-chloro-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one (4mmol, prepared in Example 14, Part 1, Step B),tetrakis(triphenylphosphine) palladium(0) (225 mg, 0.2 mmol) and aqueousK₂CO₃ (1M, 8 mL) provided7-fluoro-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-oneas a tan powder (860 mg, 69%). MS m/z 313.0 [M+H]⁺.

Step D: Following the procedure in Example 14, Part 3, Step B,7-Fluoro-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one(65 mg, 0.21 mmol) and piperazine (90 mg, 1.05 mmol) afforded the titlecompound as a tan powder (34 mg, 43%). M.P. 282-288° C.; MS m/z 379.4[M+H]⁺; ¹H NMR (DMSO-d₆, 500 MHz): δ 9.26 (1H, s), 8.21 (1H, d, J=2.6Hz), 8.10 (1H, dd, J=9.7 Hz, 2.7 Hz), 7.93 (1H, d, J=2.3 Hz), 7.84 (1H,d, J=12.7 Hz), 7.68 (1H, d, J=9.8 Hz), 6.98 (1H, s), 3.14 (4H, m), 2.88(4H, m), 2.39 (3H, s), 2.35 (1H, br s).

As shown in Table 1 below, additional compounds disclosed herein may beprepared according to Example 16 by substituting the appropriatestarting materials, reagents and reaction conditions.

Example 17 Preparation of Cpd 182

Step A: Following the procedure for Example 14, Part 3, Step A,3-fluoro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(˜4.85 mmol, crude product prepared by the procedure in Example 14, Part2) and 2-chloro-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one (0.64 g, 3.23mmol, prepared in Example 14, Part 1) gave7-fluoro-2-(5-fluoro-6-methoxypyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-4-one(1.0 g, 100%) as a brown solid, MS m/z 290.4 [M+H]⁺.

Step B: A mixture of7-fluoro-2-(5-fluoro-6-methoxypyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-4-one(145 mg, 0.5 mmol) and piperazine (43 mg, 0.5 mmol) in DMA (1 mL) washeated at 120° C. After 4 hours, the volatiles were removed and theresidue was chromatographed (20% MeOH/CH₂Cl₂) to give the title compoundas a yellow solid (63 mg, 36%). M.P. 166-170° C.; MS m/z 356.4 [M+H]⁺;¹H NMR (500 MHz, DMSO-d₆): δ 8.83 (1H, d, J=1.9 Hz), 8.39 (1H, dd, J=1.9Hz, 11.8 Hz), 8.23 (1H, d, J=2.6 Hz), 8.10 (1H, dd, J=2.7 Hz, 9.7 Hz),7.71 (1H, d, J=9.7 Hz), 7.02 (1H, s), 4.03 (3H, s), 3.20 (4H, m), 2.94(4H, m).

As shown in Table 1 below, additional compounds disclosed herein may beprepared according to Example 17 by substituting the appropriatestarting materials, reagents and reaction conditions.

Example 18 Preparation of Cpd 191

Step A: Following the procedure of Example 14, Part 3, Step A,2-chloro-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one (199 mg, 1 mmol,prepared in Example 14, Part 1),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(239.2 mg 1.15 mmol), Pd(PPh₃)₄ (57.8 mg, 0.05 mmol) and K₂CO₃ (276.4mg, 2 mmol) in CH₃CN/H₂O (1.0 mL/1.0 mL) gave7-fluoro-2-(1-methyl-1H-pyrazol-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one(97.6 mg, 40%). MS m/z 245.1 [M+H]⁺.

Step B: Following the procedure of Example 14, Part 3, Step B,7-fluoro-2-(1-methyl-1H-pyrazol-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one(48.8 mg, 0.2 mmol) and (S)-2-methylpiperazine (100 mg, 1 mmol) in DMSO(0.5 mL) gave the title compound (32.1 mg, 49.5%). M.P. 168-170° C.; MSm/z 325.2 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆): δ 8.35 (1H, s), 8.18 (1H,d, J=2.8 Hz), 8.06 (1H, s), 8.02 (1H, dd, J=9.7 Hz, 2.6 Hz), 7.56 (1H,d, J=9.8 Hz), 6.63 (1H, s), 3.89 (3H, s), 3.54-3.57 (2H, m), 2.99-3.02(1H, m), 2.80-2.85 (2H, m), 2.58-2.64 (1H, m), 2.24-2.28 (1H, m), 1.05(3H, d, J=6.3 Hz).

As shown in Table 1 below, additional compounds disclosed herein may beprepared according to Example 18 by substituting the appropriatestarting materials, reagents and reaction conditions.

Example 19 Preparation of Cpd 128

Step A: To a solution of2-chloro-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one (199 mg, 1.0 mmol,prepared in Example 14, Part 1) in 2 mL of acetonitrile were added5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine(293 mg, 1.2 mmol), tetrakistriphenylphosphine Pd (0) (57.8 mg, 0.05mmol) and aqueous K₂CO₃ (1M in water, 2 mmol) at room temperature. Themixture was stirred at 85° C. for 3 hours and cooled to roomtemperature. The solid was filtered off and washed with dichloromethane,water and acetonitrile to give7-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one(249 mg, 89%). MS m/z 281.1 [M+H]⁺.

Step B: A solution of7-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one(100 mg, 0.36 mmol) in DMSO (1 mL) was treated with piperazine (154 mg,1.79 mmol) at room temperature. The solution was stirred at 160° C. for30 minutes and cooled to room temperature. The reaction mixture wasloaded on silica gel without concentration and eluted with MeOH (0% to20%) in CH₂Cl₂ to provide the title compound (74.8 mg, 60%). M.P.252-255° C.; MS m/z 347.1 [M+H]⁺; ¹H NMR (DMSO-d₆, 500 MHz) δ 11.8 (1H,s), 8.95 (1H, d, J=2.0 Hz)), 8.64 (1H, d, J=1.7 Hz), 8.14 (1H, d, J=2.3Hz), 8.0-7.9 (1H, m), 7.62 (1H, d, J=9.6 Hz), 7.45 (1H, m), 6.9 (1H, s),6.48 (1H, br. m). 3.1 (4H, m), 2.85 (4H, m).

As shown in Table 1 below, additional compounds disclosed herein may beprepared according to Example 19 by substituting the appropriatestarting materials, reagents and reaction conditions.

Example 20 Preparation of Cpd 153

Step A:2-(3-Fluoro-4-hydroxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one(180 mg, 0.53 mmol), prepared by Suzuki coupling according to theprocedure in Example 14, Part 3, Step A, was combined with di-tert-butyldicarbonate (131 mg, 0.6 mmol) and triethylamine (85 μL, 0.6 mmol) inMeOH (4 mL). The mixture was stirred at 50° C. for 2 hours. The mixturewas filtered, leaving a yellow powder, which was washed with MeOH anddried under vacuum, affording tert-butyl4-(2-(3-fluoro-4-hydroxyphenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)piperazine-1-carboxylate(230 mg, 99%). MS m/z 441.0 [M+H]⁺.

Step B: tert-Butyl4-(2-(3-fluoro-4-hydroxyphenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)piperazine-1-carboxylate(60 mg, 0.14 mmol) was combined with K₂CO₃ (39 mg, 0.28 mmol) andiodoethane (48 μL, 0.21 mmol) in DMF (1 mL). The mixture was stirred at50° C. for 1 hour. After cooling to room temperature, H₂O (0.5 mL) wasadded drop wise to the mixture. The precipitate was collected, washedwith H₂O, and dried under vacuum.

Step C: To the crude product from Step B was added trifluoroacetic acid(1 mL). After standing for 10 minutes, volatiles were removed. Theresidue was partitioned in CH₂Cl₂ (4 mL) and aqueous K₂CO₃ (1M, 2 mL).The organic layer was removed and concentrated, providing the titlecompound (36 mg, 70%). M.P. 180-186° C.; MS m/z 369.1 [M+H]⁺; ¹H NMR(DMSO-d₆, 500 MHz): δ 8.21 (1H, d, J=2.7 Hz), 8.02 (3H, m), 7.68 (1H, d,J=9.7 Hz), 7.27 (1H, t, J=8.8 Hz), 6.93 (1H, s), 4.20 (2H, q, J=7.0 Hz),3.14 (4H, m), 2.88 (4H, m), 2.36 (1H, br), 1.39 (3H, t, J=7.0 Hz).

As shown in Table 1 below, additional compounds disclosed herein may beprepared according to Example 20 by substituting the appropriatestarting materials, reagents and reaction conditions.

Example 21 Preparation of Cpd 179

Step A: A mixture of 2-chloro-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one(300 mg, 1.5 mmol) and 4-methyl-1H-imidazole (429 mg, 6.0 mmol) in DMSO(1.5 mL) was heated at 90° C. for 15 hours. The mixture was cooled toroom temperature and diluted with CH₃CN. The precipitate was filtered,washed with CH₃CN (3×) and dried to give2-(4-methyl-1H-imidazol-1-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-oneas an off-white solid (225 mg, 61%). MS m/z 345.4 [M+H]⁺.

Step B: A mixture of2-(4-methyl-1H-imidazol-1-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one(73 mg, 0.3 mmol) and piperazine (129 mg, 1.5 mmol) in DMA (0.6 mL) washeated at 120° C. for 4 hours. The DMA was removed and the mixture wasdiluted with CH₃CN. The precipitate was filtered, washed with CH₃CN (3×)and dried to give the title compound as a yellow solid (310 mg, 95%).M.P. 204-206° C.; MS m/z 311.1 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆): δ 8.47(1H, d, J=1.2 Hz), 8.22 (1H, d, J=2.7 Hz), 8.13 (1H, dd, J=2.8 Hz, 9.6Hz), 7.69 (1H, d, J=1.1 Hz), 7.63 (1H, d, J=9.6 Hz), 6.68 (1H, s), 3.14(4H, m), 2.87 (4H, m), 2.16 (3H, s).

As shown in Table 1 below, additional compounds disclosed herein may beprepared according to Example 21 by substituting the appropriatestarting materials, reagents and reaction conditions.

Example 22 Preparation of Cpd 143

Step A: Following the procedure in Example 1, Step A, methyl3-(3,4-dimethoxyphenyl)-3-oxopropanoate (5.0 gram, 20 mmol),trimethylorthoformate (3.5 mL, 30 mmol) and p-toluenesulfonic acidmonohydrate (380 mg, 2 mmol) in methanol (50 mL) provided methyl3-(3,4-dimethoxyphenyl)-3,3-dimethoxypropanoate. The crude product wasused directly in the next step without purification. ¹H NMR (DMSO-d₆,500 MHz): δ 6.93 (3H, m), 3.82 (2H, q, J=7.2 Hz), 3.75 (3H, s), 3.73(3H, s), 3.12 (6H, s), 2.92 (2H, s), 0.92 (3H, t, J=7.1 Hz).

Step B: To the above ketal intermediate was added 5-bromopyridin-2-amine(3.5 g, 20 mmol). The mixture was heated to 150° C. for 2 hours, thencooled to room temperature. The crude product was triturated withacetonitrile and filtered to provide the title compound as a white solid(6.8 gram, 94%). MS m/z 360.9 [M+H]⁺, 362.9 [M+2+H]⁺.

Step C: Following the procedure in Example 14, Part 3, Step A,7-bromo-2-(3,4-dimethoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one (181 mg,0.5 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(170 mg, 0.55 mmol), potassium carbonate (207 mg, 1.5 mmol) andPd(dppf)Cl₂ (36.5 mg, 0.05 mmol) in acetonitrile (2 mL) providedtert-butyl4-(2-(3,4-dimethoxyphenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylateas a white solid (0.22 mg, 95%). MS m/z 464.1 [M+H]⁺; ¹H NMR (500 MHz,DMSO-d₆) δ 8.82 (s, 1H), 8.24 (dd, J=1.5, 9 Hz, 1H), 7.85 (dd, J=2, 8.5Hz, 1H), 7.78 (d, J=2 Hz, 1H), 7.73 (d, J=9.5 Hz, 1H), 7.10 (d, J=9 Hz,1H), 7.05 (s, 1H), 6.54 (s, 1H), 4.09 (bs, 2H), 3.89 (s, 3H), 3.85 (s,3H), 3.60-3.59 (m, 2H), 2.64-2.63 (m, 2H), 1.45 (s, 9H).

Step D: The intermediate obtained from Step A was suspended in asolution of HCl in dioxane (4M, 4 mL). The reaction mixture was stirredat room temperature for 2 hours. The mixture was concentrated and theresidue was partitioned between dichloromethane and saturated aqueoussodium bicarbonate. The organics were dried, concentrated andchromatographed on a basic alumina column, eluting with dichloromethanewith methanol (10%) to provide the title compound as a white solid (150mg, 88%). M.P. 196-198° C.; MS m/z 364.1 [M+H]⁺; ¹H NMR (500 MHz,DMSO-d₆) δ 8.77 (d, J=2 Hz, 1H), 8.24 (dd, J=2, 9.5 Hz, 1H), 7.85 (dd,J=2, 8.5 Hz, 1H), 7.78 (d, J=2 Hz, 1H), 7.71 (d, J=9.5 Hz, 1H), 7.09 (d,J=8.5 Hz, 1H), 7.03 (s, 1H), 6.60 (s, 1H), 3.89 (s, 3H), 3.85 (s, 3H),3.45 (d, J=2.5 Hz, 2H), 2.97 (t, J=5.5 Hz, 2H), 2.41 (bs, 2H).

As shown in Table 1 below, additional compounds disclosed herein may beprepared according to Example 22 by substituting the appropriatestarting materials, reagents and reaction conditions.

Example 23 Preparation of Cpd 188

A mixture of2-(3,4-dimethoxyphenyl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one(30 mg, 0.08 mmol), formaldehyde (0.05 mL, 37%, ˜0.8 mmol) and sodiumtriacetoxyborohydride (50 mg, 0.24 mmol) was stirred in dichloromethane(1 mL) for 2 hr. The reaction mixture was diluted with dichloromethaneand neutralized with sodium bicarbonate. The organics were dried andconcentrated to provide the title compound as a white solid (26 mg,83%). M.P. 165-168° C.; MS m/z 378.4 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ8.79 (d, J=2 Hz, 1H), 8.25 (dd, J=2, 9.5 Hz, 1H), 7.85 (dd, J=2, 8.5 Hz,1H), 7.78 (d, J=2 Hz, 1H), 7.71 (d, J=9.5 Hz, 1H), 7.10 (d, J=8.5 Hz,1H), 7.04 (s, 1H), 6.56 (s, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 3.09 (bs,2H), 2.64-2.61 (m, 2H), 2.56 (bs, 2H), 2.51 (s, 3H).

As shown in Table 1 below, additional compounds disclosed herein may beprepared according to Example 23 by substituting the appropriatestarting materials, reagents and reaction conditions.

Example 24 Preparation of Cpd 144

Step A: A mixture of tert-butyl4-(2-(3,4-dimethoxyphenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylate(100 mg, 0.22 mmol, prepared as depicted in Example 22, Step C) and Pd/C(10%) (10 mg) in ethyl acetate (25 mL) was stirred under 1 atmosphere ofhydrogen overnight. The reaction mixture was filtered through celite,concentrated and chromatographed on a silica column, eluting withEtOAc/CH₂Cl₂ (30/70) to provide tert-butyl4-(2-(3,4-dimethoxyphenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)piperidine-1-carboxylateas a white solid (75 mg, 75%), which was used directly in the next stepwithout further purification. MS m/z 466.4 [M+H]⁺; ¹H NMR (500 MHz,DMSO-d₆) δ 8.57 (s, 1H), 7.80 (dd, J=2.5, 9.5 Hz, 1H), 7.64 (dd, J=2,8.5 Hz, 1H), 7.57 (d, J=2 Hz, 1H), 7.53 (d, J=9 Hz, 1H), 6.9 (d, J=9 Hz,1H), 6.82 (s, 1H), 3.92 (bs, 2H), 3.69 (s, 3H), 3.65 (s, 3H), 2.78-2.71(m, 2H), 2.69-2.65 (1H, m), 1.69-1.67 (m, 2H), 1.41-1.38 (m, 2H), 1.24(s, 9H).

Step B: Following the procedure in Example 22, Step D, the above productfrom Step A and HCl in dioxane (4M, 3 mL) provided the title compound asa white solid (49 mg, 83%). M.P. 214-217° C.; MS m/z 366.4 [M+H]⁺; ¹HNMR (500 MHz, DMSO-d₆) δ 8.88 (d, J=2 Hz, 1H), 8.09 (dd, J=2, 9.5 Hz,1H), 7.98 (dd, J=2, 8.5 Hz, 1H), 7.91 (d, J=2 Hz, 1H), 7.88 (d, J=9 Hz,1H), 7.23 (d, J=8.5 Hz, 1H), 7.15 (s, 1H), 4.02 (s, 3H), 3.98 (s, 3H),3.30 (d, J=11.5 Hz, 2H), 3.01 (tt, J=2 Hz, 12 Hz, 1H), 2.87 (t, J=12 Hz,2H), 2.02 (d, J=12.5 Hz, 2H), 1.80-1.73 (m, 2H).

Example 25 Preparation of Cpd 164

Following the procedure in Example 23,2-(3,4-dimethoxyphenyl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one(10 mg, 0.027 mmol), formaldehyde (10 μL, 37%, 0.13 mmol) and sodiumtriacetoxyborohydride (17 mg, 5.7 mmol) in dichloromethane (0.5 mL)provided the title compound as a white solid (7.6 mg, 73%). M.P.181-183° C.; MS m/z 380.1 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 8.76 (d,J=2 Hz, 1H), 8.0 (dd, J=2, 9 Hz, 1H), 7.84 (dd, J=2, 8.5 Hz, 1H), 7.77(d, J=2 Hz, 1H), 7.72 (d, J=9.5 Hz, 1H), 7.09 (d, J=8.5 Hz, 1H), 7.01(s, 1H), 3.89 (s, 3H), 3.84 (s, 3H), 2.91 (d, J=9.5 Hz, 2H), 2.73-2.64(m, 1H), 2.22 (s, 3H), 2.01 (t, J=8.5 Hz, 2H), 1.88-1.85 (m, 2H),1.71-1.69 (m, 2H).

As shown in Table 1 below, additional compounds disclosed herein may beprepared according to Example 25 by substituting the appropriatestarting materials, reagents and reaction conditions.

Example 26 Preparation of Cpd 263

Part 1: Following the procedure in Example 14, Part 2,7-Bromo-2-(3,4-dimethoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one (661 mg,1.8 mmol), prepared in Example 22, Step B, KOAc (530 mg, 5.4 mmol),bis(pincolato)diboron (700 mg, 2.7 mmol), and Pd(dppf)Cl₂ (60 mg, 0.09mmol) in dioxane (5 mL) provided2-(3,4-dimethoxyphenyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-oneas a white solid (560 mg, 76%). MS m/z 327.1 [M+H]⁺ for boronic acid.

Part 2: To a solution of tert-butyl 3-oxopiperidine-1-carboxylate (482mg, 2.4 mmol) in 2-methyltetrahydrofuran (2.5 mL) was added drop wise asolution of sodium bis(trimethylsilyl)amide (2.6 mL, 2.6 mmol, 1.0M inTHF) at −78° C. under argon. The mixture was stirred at −78° C. for 1hr, followed by the addition of a solution ofN-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-(trifluoromethylsulfonyl)-methanesulfonamide(1.0 gram, 2.5 mmol) in 2-methyltetrahydrofuran (2.5 mL), and then thereaction was allowed to warm to room temperature over 2 hours. Afterstirring at room temperature overnight, the reaction was quenched withsaturated aqueous sodium carbonate, diluted with ether, and the organicswere washed with water, dried and concentrated. The crude product waschromatographed on a basic alumina column, eluting with 5% ethyl acetatein hexane to provide the title compound as a colorless oil (290 mg,37%).

Part 3, Step A: Following the procedure of Example 14, Part 3, Step A,2-(3,4-dimethoxyphenyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one(370 mg, 0.91 mmol), tert-butyl3-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate(290 mg, 0.88 mmol), potassium carbonate (364 mg, 2.6 mmol) andPd(dppf)Cl₂ (58 mg, 0.08 mmol) in acetonitrile (4 mL) providedtert-butyl3-(2-(3,4-dimethoxyphenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylateas a white solid (0.22 mg, 62%). MS m/z 464.3 [M+H]⁺.

Part 3, Step B: Following the procedure in Example 22, Step B,tert-butyl3-(2-(3,4-dimethoxyphenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylate(220 mg, 0.47 mmol) and HCl in dioxane (4M, 5 mL) provided the titlecompound (160 mg, 79%). M.P. 146-150° C.; MS m/z 364.2 [M+H]⁺; ¹H NMR(500 MHz, DMSO-d₆) δ 8.73 (d, J=2 Hz, 1H), 8.23 (dd, J=2, 9.5 Hz, 1H),7.85 (dd, J=2, 8.5 Hz, 1H), 7.78 (d, J=2.5 Hz, 1H), 7.71 (d, J=9.5 Hz,1H), 7.10 (d, J=8.5 Hz, 1H), 7.05 (s, 1H), 6.60 (s, 1H), 3.89 (s, 3H),3.85 (s, 3H), 3.29 (bs, 2H), 2.40-2.36 (m, 4H).

Example 27 Preparation of Cpd 237

Step A: NaH (60% dispersion in mineral oil, 12 mg, 0.3 mmol) was addedslowly to 1-Boc-4-hydroxypiperidine (48.3 mg, 0.24 mmol) in anhydrousTHF at room temperature. The reaction mixture was stirred at roomtemperature for 10 minutes, and2-(3,4-dimethoxyphenyl)-7-F-4H-pyrido[1,2-a]pyrimidin-4-one (60 mg, 0.2mmol) was added. The reaction mixture was then heated at 70° C. for 3hours. A small amount of ice water was added to quench the reaction.After most of the THF was evaporated, ether was added to the mixture,and the precipitate was filtered and dried to provide tert-butyl4-(2-(3,4-dimethoxyphenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yloxy)piperidine-1-carboxylate,which was used in the next step without further purification.

Step B: tert-Butyl4-(2-(3,4-dimethoxyphenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yloxy)piperidine-1-carboxylatewas dissolved into CH₂Cl₂/TFA (0.5 mL/0.5 mL) at 0° C. The mixture wasstirred at 0° C. for 2 hours, until the starting material disappeared.After most of the TFA was evaporated, ice cold saturated NaHCO₃ wasadded to the reaction mixture. The mixture was extracted with CH₂Cl₂.The organic layer was dried over MgSO₄ and concentrated to provide thetitle compound (57 mg, 74.8% for 2 steps). M.P. 221-224° C.; MS m/z382.2 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆): δ 8.58 (1H, d, J=2.9 Hz),7.81-7.86 (2H, m), 7.73-7.78 (2H, m), 7.08 (1H, d, J=8.7 Hz), 7.01 (1H,s), 4.82-4.86 (1H, m), 3.87 (3H, s), 3.83 (3H, s), 3.23-3.27 (2H, m),3.04-3.09 (2H, m), 2.13-2.18 (2H, m), 1.85-1.91 (2H, m).

As shown in Table 1 below, additional compounds disclosed herein may beprepared according to Example 27 by substituting the appropriatestarting materials, reagents and reaction conditions.

Example 28 Preparation of Cpd 52

Step A: Ethyl 2-(3,4-dimethoxyphenyl)acetate (673 mg, 3 mmol) wascombined with 1-tert-butoxy-N,N,N′,N′-tetramethylmethanediamine (0.68mL, 3.3 mmol). The mixture was heated to 60° C. for 2 hours. The mixturewas used directly in the next step without work-up.

Step B: 4-Chloropyridin-2-amine (424 mg, 3.3 mmol) was added directly tothe mixture. The mixture was heated to 120° C. for 20 minutes. Themixture was used directly in the next step without work-up.

Step C: Piperazine (1.3 g, 15 mmol) was added to the mixture from StepB, which stirred for an additional 30 minutes at 120° C. The mixture waschromatographed on silica with 10% MeOH (1% triethylamine) in CH₂Cl₂affording the title compound as a yellow powder (120 mg, 11%). M.P.175-179° C.; MS m/z 367.2 [M+H]⁺; ¹H NMR (DMSO-d₆, 500 MHz): δ 8.84 (1H,d, J=8.2 Hz), 8.40 (1H, s), 7.44 (1H, d, J=2.1 Hz), 7.34 (1H, dd, J=8.4Hz, 2.1 Hz), 7.28 (1H, dd, J=8.2 Hz, 2.8 Hz), 6.99 (1H, d, J=8.5 Hz),6.73 (1H, d, J=2.8 Hz), 3.80 (3H, s), 3.78 (3H, s), 3.48 (4H, m), 2.82(4H, m).

Example 29 Preparation of Cpd 220

Step A: 7-Bromo-2-chloro-4H-pyrido[1,2-a]pyrimidin-4-one (130 mg, 0.5mmol), prepared according to Example 14, Part 1, was combined withtert-butyl piperazine-1-carboxylate (140 mg, 0.75 mmol) andtriethylamine (0.14 mL, 1.0 mmol) in EtOH (2 mL). The mixture was heatedto 80° C. for 1 hour. The reaction mixture was cooled to roomtemperature, and then filtered. The collected material waschromatographed on silica with 0% to 50% EtOAc in CH₂Cl₂, providingtert-butyl4-(7-bromo-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)piperazine-1-carboxylate(130 mg, 64%). MS m/z 409.4 [M+H]⁺.

Step B: The intermediate (0.3 mmol) from Step A was combined with3-fluoro-4-methoxyphenylboronic acid (77 mg, 0.45 mmol) andtetrakis(triphenylphosphine) palladium(0) (35 mg, 0.03 mmol) in CH₃CN (2mL) and aqueous K₂CO₃ (1M, 2 mL). The mixture was heated at 80° C. withvigorous stirring under argon for 2 hours. The organic layer was removedand concentrated. The residue was chromatographed on silica with 0% to50% EtOAc in CH₂Cl₂.

Step C: The Boc-protected intermediate from Step B was dissolved intrifluoroacetic acid (1 mL). After 20 minutes, volatiles were removed.The residue was partitioned in CH₂Cl₂ and aqueous K₂CO₃ (1M). Theorganic layer was removed and concentrated, affording the title compoundas a white powder (30 mg, 17%). M.P. 202-206° C.; MS m/z 355.0 [M+H]⁺;¹H NMR (DMSO-d₆, 500 MHz): δ 8.93 (1H, d, J=2.0 Hz), 8.15 (1H, dd, J=9.3Hz, 2.3 Hz), 7.67 (1H, dd, J=12.7 Hz, 2.3 Hz), 7.54 (1H, m), 7.37 (1H,d, J=9.2), 7.30 (1H, t, J=8.8 Hz), 5.62 (1H, s), 3.90 (3H, s), 3.57 (4H,m), 2.75 (4H, m), 2.42 (1H, br s).

As shown in Table 1 below, additional compounds disclosed herein may beprepared according to Example 29 by substituting the appropriatestarting materials, reagents and reaction conditions.

Example 30 Preparation of Cpd 276

Step A. 7-Bromo-2-chloro-4H-pyrido[1,2-a]pyrimidin-4-one (1.29 g, 5mmol) was combined with 3-fluoro-4-methoxyphenylboronic acid (850 mg, 5mmol), tetrakis(triphenylphosphine) palladium(0) (281 mg, 0.25 mmol),CH₃CN (10 mL) and aqueous K₂CO₃ (1M, 10 mL). The mixture was heated to80° C. for 6 hours. After cooling to room temperature, the mixture waspartitioned in CH₂Cl₂ (75 mL) and H₂O (50 mL). The organic layer wascollected and concentrated. The residue was chromatographed on silica,eluting with EtOAc (0% to 50%) in CH₂Cl₂, to afford2-chloro-7-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one asa white powder (520 mg, 34%). MS m/z 305.0 [M+H]⁺.

Step B.2-Chloro-7-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one(180 mg, 0.6 mmol) was combined with 4-aminopiperidine (90 mg, 0.9 mmol)and triethylamine (165 μL, 1.2 mmol) in DMSO (0.75 mL). The mixture washeated to 120° C. for 30 minutes. After cooling to room temperature,CH₃CN (2 mL) was added to the mixture. The mixture was filtered. Thecollected material was washed with CH₃CN and dried under vacuum,affording the title compound as a white powder (115 mg, 52%). M.P.268-283° C.; MS m/z 369.3 [M+H]⁺; ¹H NMR (DMSO-d₆, 500 MHz): δ 8.94 (1H,d, J=2.0 Hz), 8.16 (1H, dd, J=9.3 Hz, 2.3 Hz), 7.68 (1H, dd, J=12.7 Hz,2.3 Hz), 7.55 (1H, d, J=8.5 Hz), 7.39 (1H, d, J=9.2), 7.30 (1H, t, J=8.9Hz), 5.70 (1H, s), 5.20 (2H, br), 4.36 (2H, br), 3.92 (3H, s), 3.04 (3H,m), 1.87 (2H, m), 1.32 (2H, m).

As shown in Table 1 below, additional compounds disclosed herein may beprepared according to Example 30 by substituting the appropriatestarting materials, reagents and reaction conditions.

Example 31 Preparation of Cpd 85

Part 1, Step A: To a suspension of MgCl₂ (2.85 g, 30 mmol) inacetonitrile (27 mL) at 0° C. was added dropwise diethyl malonate (3.4mL, 30 mmol) and triethylamine (8.3 mL, 60 mmol). The mixture wasstirred at 0° C. for 30 minutes. 3,4-dimethoxybenzoyl chloride (5.0 g,25 mmol) was then added portionwise. The mixture was allowed to stir atroom temperature overnight, after which it was treated with 1N HCl,extracted with ether, dried and evaporated. The residue was purified onsilica with ethyl acetate (5% to 40%) in hexanes to give dimethyl2-(3,4-dimethoxybenzoyl)malonate (7.38 g, 100%). MS m/z 297.1 [M+H]⁺.

Part 1, Step B: To a solution of dimethyl2-(3,4-dimethoxybenzoyl)malonate (2.96 g, 10 mmol) in POCl₃ (9.4 mL, 100mmol) at room temperature was added DIPEA (2.75 mL, 16.7 mmol) dropwise.The mixture was then stirred at 100° C. for 3 hours. POCl₃ was removedunder vacuum and the residue was treated with ice-water and extractedwith ether. The organic layer was washed with 1N HCl, dried andevaporated. The residue was purified on silica with ethyl acetate (5% to50%) in hexanes to give the title compound (2.0 g, 64%). MS m/z 282.9[M+H]⁺.

Part 2: To a solution of LDA (1.5 M, 13.3 mL, 20 mmol) in THF (15 mL) at−78° C. was added dropwise a solution of 2,5-difluoropyridine (1.15 g,10 mmol) in THF (10 mL). The temperature was then allowed to rise toroom temperature, and the mixture was stirred at room temperature for 2hours before the reaction was quenched with aqueous NH4Cl. The mixturewas extracted with ethyl acetate, dried, and evaporated. The residue waspurified on silica with ethyl acetate (5% to 50%) in hexanes to give2-(5-fluoropyridin-2-yl)acetonitrile (0.8 g, 59%). MS m/z 137.0 [M+H]⁺.

Part 3, Step A: To a solution of 2-(5-fluoropyridin-2-yl)acetonitrile(44 mg, 0.325 mmol) in DMF (0.5 mL) was added 60% NaH (20 mg, 0.325mmol). The mixture was stirred at room temperature for 10 minutes andthen treated with dimethyl2-(chloro(3,4-dimethoxyphenyl)methylene)malonate (102 mg, 0.325 mmol).The mixture was stirred for 15 minutes, and the reaction was quenchedwith saturated NH₄Cl solution. The mixture was filtered. The solid waswashed with water and used directly in the next step without furtherpurification.

Part 3, Step B: The crude solid from Step A was treated with TFA (2.0mL) and water (0.2 mL). The mixture was stirred at 100° C. overnight.The solvent was then removed under vacuum and the crude product was usedin the next step without further purification.

Part 3, Step C: The crude product from Step B was heated with piperazine(86 mg, 1.0 mmol) in DMSO (1.0 mL) at 120° C. overnight. Removal of thesolvent by N₂ followed by purification over silica with methanol (10%)in dichloromethane provided the title compound (30 mg, 25%). M.P.199-202° C.; MS m/z 391.2 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃) δ: 8.60 (1H,d, J=2.2 Hz), 7.98 (1H, d, J=9.8 Hz), 7.59 (1H, dd, J=9.5, 2.5 Hz), 7.20(1H, dd, J=8.5, 2.2 Hz), 7.12 (1H, d, J=2.2 Hz), 6.93 (1H, d, J=8.2 Hz),6.52 (1H, s), 3.89 (3H, s), 3.88 (3H, s), 3.23-3.21 (4H, m), 3.05-3.03(4H, m).

Example 32 Preparation of Cpd 91

Step A: To a solution of 2-(5-fluoropyridin-2-yl)acetonitrile (0.78 g,5.7 mmol) in MeOH (15 mL) was added trimethysilyl chloride (4.4 mL, 34.4mmol) dropwise. The mixture was stirred at 50° C. overnight. Organicvolatiles were removed under vacuum and the residue was partitionedbetween ether and aqueous sodium bicarbonate. The aqueous layer wasextracted with ether. The ether extractions were combined, dried andevaporated to give methyl 2-(5-fluoropyridin-2-yl)acetate as an oil (0.9g, 93%), which was used without further purification. MS m/z 170.1[M+H]⁺.

Step B: Following the procedure in Example 31, Part 3, Step A, methyl2-(5-fluoropyridin-2-yl)acetate (0.34 g, 2.0 mmol), 60% NaH (176 mg, 4.4mmol) and dimethyl 2-(chloro(3,4-dimethoxyphenyl)methylene)malonate(0.69 g, 2.2 mmol, prepared in Example 31, Part 1, Step B) in DMF (3.0mL) provided the desired dimethyl2-(3,4-dimethoxyphenyl)-7-fluoro-4-oxo-4H-quinolizine-1,3-dicarboxylate(0.2 g, 24%). MS m/z 416.1 [M+H]⁺.

Step C: A solution of dimethyl2-(3,4-dimethoxyphenyl)-7-fluoro-4-oxo-4H-quinolizine-1,3-dicarboxylate(0.2 g, 0.48 mmol) in methanol (6.0 mL) was treated with aqueous LiOH(2.0 N, 2.0 mL, 4.0 mmol) and stirred at 90° C. for 2 hours. Aqueousworkup followed by evaporation provided a dark residue, which wastreated with TFA (2.0 mL) and water (0.2 mL) and stirred at 100° C. for1 hour. Removal of the solvents by N₂ followed by chromatography withethyl acetate (25% to 75%) in hexanes provided2-(3,4-dimethoxyphenyl)-7-fluoro-4H-quinolizin-4-one (30 mg, 21%). MSm/z 300.2 [M+H]⁺.

Step D: A solution of2-(3,4-dimethoxyphenyl)-7-fluoro-4H-quinolizin-4-one (30 mg, 0.1 mmol),(S)-2-methyl piperazine (30 mg, 0.3 mmol) and K₂CO₃ (27 mg, 0.2 mmol) inDMSO (0.2 mL) was stirred at 120° C. for 48 hours. Removal of thesolvents by N₂ followed by purification by dichloromethane and methanol(10%) provided the title compound (24 mg, 63%). M.P. 243-245° C.; MS m/z380.2 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃) δ: 8.52 (1H, d, J=2.2 Hz), 7.46(1H, d, J=9.8 Hz), 7.30 (2H, dt, J=10.4, 2.2 Hz), 7.22 (1H, d, J=1.9Hz), 6.98 (1H, d, J=8.5 Hz), 6.84 (2H, s), 3.96 (3H, s), 3.95 (3H, s),3.58-3.54 (2H, m), 3.50 (1H, s), 3.21-3.19 (1H, m), 3.12-3.04 (2H, m),2.85-2.80 (1H, m), 2.49 (1H, t, J=11.1 Hz), 1.20 (3H, d, J=6.6 Hz).

Example 33 Preparation of Cpd 106

Step A: To a mixture of Pd₂(dba)₃ (0.55 g, 0.6 mmol) and DavePhos (0.50g, 1.26 mmol) in toluene (40 mL) at room temperature under an argonatmosphere was added a solution of LHMDS in hexane (1.0 M×50 mL, 50mmol) dropwise. The mixture was stirred for 10 minutes and then cooledto −10° C., into which tert-butyl acetate (6.2 mL, 46 mmol) was addedand stirred for another 10 minutes. 2-Bromo-5-fluoropyridine (3.52 g, 20mmol) was then added portionwise. Upon completion of the addition, thetemperature was allowed to rise to room temperature and the mixture wasstirred for another 1 hour. The reaction was then quenched by saturatedNH₄Cl solution. Aqueous workup followed by chromatography with ethylacetate (0% to 20%) in hexanes provided tert-butyl2-(5-fluoropyridin-2-yl)acetate (2.6 g, 62%).

Step B: Following the procedure in Example 31 Part 3, Step A, tert-butyl2-(5-fluoropyridin-2-yl)acetate, 60% NaH (80 mg, 2.0 mmol) and dimethyl2-(chloro(3,4-dimethoxyphenyl)-methylene)malonate (0.32 g, 1.0 mmol,prepared in Example 31, Part 2, Step B) in DMF (1.0 mL) provided1-tert-butyl 3-methyl2-(3,4-dimethoxyphenyl)-7-fluoro-4-oxo-4H-quinolizine-1,3-dicarboxylate.The crude solid was used directly in the next step without purification.

Step C: Following the procedure in Example 31 Part 3, Step B, The crudesolid from Step B, TFA (5 mL) and water (2 mL) provided2-(3,4-dimethoxyphenyl)-7-fluoro-4H-quinolizin-4-one (145 mg, 48%). MSm/z 300.2 [M+H]⁺.

Step D: Following the procedure in Example 31 Part 3, Step C,2-(3,4-dimethoxyphenyl)-7-fluoro-4H-quinolizin-4-one (75 mg, 0.25 mmol)and piperazine (75 mg, 0.87 mmol) in DMSO (0.5 mL) provided the titlecompound (30 mg, 33%). M.P. 170-172° C.; MS m/z 366.1 [M+H]⁺; ¹H NMR(500 MHz, CDCl₃) δ: 8.53 (1H, d, J=2.2 Hz), 7.46 (1H, d, J=9.5 Hz),7.32-7.27 (2H, m), 7.22 (1H, d, J=1.9 Hz), 6.97 (1H, d, J=8.5 Hz), 6.84(2H, s), 3.98 (3H, s), 3.95 (3H, s), 3.25-3.20 (4H, m), 3.13-3.07 (4H,m).

As shown in Table 1 below, additional compounds disclosed herein may beprepared according to Example 33 by substituting the appropriatestarting materials, reagents and reaction conditions.

Example 34 Preparation of Cpd 245

Step A: A mixture of 5-bromo-2-iodopyridine (2.84 g, 10 mmol),tert-butyl ethyl malonate (3.76 g, 20 mmol), Cs₂CO₃ (9.77 g, 30 mmol),CuI (0.19 g, 1.0 mmol) and 2-nicotinic acid (0.246 g, 2.0 mmol) indioxane (20 mmol) was stirred at 90° C. overnight under nitrogenatmosphere. The mixture was then treated with water, extracted withethyl acetate, dried and evaporated. The residue was dissolved in MeOH(100 mL) and water (40 mL) and NaOH (1.2 g, 30 mmol) were added. Themixture was stirred at room temperature for 3 hours, then acidified with1N HCl to pH 4, extracted with ethyl acetate, dried and chromatographedwith ethyl acetate (10% to 50%) in hexanes to give tert-butyl2-(5-bromopyridin-2-yl)acetate (1.2 g, 44%).

Step B: Following the procedure in Example 33, Step B and C, tert-butyl2-(5-bromopyridin-2-yl)acetate (0.54 g, 2.0 mmol) was treated with NaH(60% in mineral oil, 0.16 g, 4.0 mmol) in DMF (2.0 mL) followed byreaction with 2-(chloro(3,4-dimethoxyphenyl)methylene)malonate (2.0mmol). Deprotection and decarboxylation in TFA (5.0 mL) and water (2.0mL) at 100° C. afforded7-bromo-2-(3,4-dimethoxyphenyl)-4H-quinolizin-4-one (0.17 g, 68%). MSm/z 360.1 [M+H]⁺, 362.0 [M+2+H]⁺.

Step C: A mixture of 7-bromo-2-(3,4-dimethoxyphenyl)-4H-quinolizin-4-one(0.17 g, 0.47 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(0.18 g, 0.57 mmol), PdCl₂dppf (38 mg, 0.047 mmol), K₂CO₃ (2.0 M×0.75mL, 1.5 mmol) in acetonitrile (1.5 mL) was stirred at 100° C. for 16hours. The mixture was then treated with water, extracted withdichloromethane, dried and chromatographed with ethyl acetate (20% to100%) in dichloromethane to give tert-butyl4-(2-(3,4-dimethoxyphenyl)-4-oxo-4H-quinolizin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylate(0.16 g, 73%). MS m/z 463.3 [M+H]⁺.

Step D: tert-butyl4-(2-(3,4-dimethoxyphenyl)-4-oxo-4H-quinolizin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylate(80 mg, 0.17 mmol) was treated with dichloromethane (1.0 mL) and TFA(1.0 mL) and stirred at room temperature for 1 hour. The mixture wasthen evaporated, treated with dichloromethane and washed with saturatedaqueous sodium bicarbonate solution. The organic layer was dried andevaporated to give the title compound (63 mg, 100%). M.P. 174-176° C.;MS m/z 363.2 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃) δ: 9.04 (1H, s), 7.53 (1H,dd, J=9.2, 1.9 Hz), 7.47 (1H, d, J=9.2 Hz), 7.31 (1H, dd, J=8.5, 2.2Hz), 7.23 (1H, d, J=2.2 Hz), 6.99 (1H, J=8.2 Hz), 6.86 (2H, br s), 6.36(1H, s), 3.99 (3H, s), 3.97 (3H, s), 3.67-3.60 (2H, m), 3.24-3.13 (2H,m), 2.62-2.55 (2H, m), 2.21 (1H, br s).

Example 35 Preparation of Cpd 249

Following the procedure in Example 23,2-(3,4-dimethoxyphenyl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-quinolizin-4-one(30 mg, 0.083 mmol), sodium triacetoxyborohydride (53 mg, 0.25 mmol) andaqueous solution of formaldehyde (30%, 14 μL, 0.166 mmol) in 10%methanol in dichloromethane (1.0 mL) gave the title compound (26 mg,83%). M.P. 194-196° C.; MS m/z 377.2 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃) δ:9.03 (1H, s), 7.51-7.44 (2H, m), 7.29 (1H, dd, J=8.5, 2.2 Hz), 7.21 (1H,d, J=1.9 Hz), 6.98 (1H, J=8.2 Hz), 6.87-6.82 (2H, m), 6.26 (1H, s), 3.98(3H, s), 3.95 (3H, s), 3.48 (2H, br s), 3.06-2.97 (2H, m), 2.90-2.80(2H, m), 2.65 (3H, s).

Example 36 Preparation of Cpd 306

Part 1, Step A: To a solution of 2-(benzyloxy)-4-bromo-6-fluoroaniline(3.74 g, 12.6 mmol) in THF (25 mL), prepared from1,3-difluoro-2-nitrobenzene in 3 steps according to known procedures(WO2007/067612), was added PtO₂ (0.23 g, 1.0 mmol). After stirring underhydrogen (1 atm, balloon) at room temperature for 23 hours, the mixturewas filtered through celite. The filtrate was concentrated to give2-amino-5-bromo-3-fluorophenol as a brown solid, which was used in thenext step without further purification. MS m/z 206.1 [M+H]⁺, 208.0[M+2+H]⁺.

Part 1, Step B: To a solution of the crude2-amino-5-bromo-3-fluorophenol from Step A in 1,1,1-triethoxyethane (10mL) was added TFA (0.96 mL, 12.6 mmol) at room temperature. After 15hours, the mixture was neutralized with Na₂CO₃ and filtered. Thefiltrated was concentrated and chromatographed with CH₂Cl₂ to give6-bromo-4-fluoro-2-methylbenzo[d]oxazole as a tan solid (2.531 g, 88%).MS m/z 230.0 [M+H]⁺, 232.1 [M+2+H]⁺.

Part 1, Step C: A mixture of 6-bromo-4-fluoro-2-methylbenzo[d]oxazole(2.531 g, 11.0 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (3.087 g,12.2 mmol), KOAc (3.25 g, 33.2 mmol) and Pd(dppf)Cl₂.CH₂Cl₂ (449 mg,0.55 mmol) in dioxane (25 mL) was degassed and heated under N₂ at 85° C.After 15 hours, LC-MS indicated disappearance of the starting materialand the products as a mixture of boronic acid and boronic pinacol esterin a ratio of ˜2/1:boronic acid product: MS m/z 196.1 [M+H]⁺; pinacolboronic ester product: MS m/z 278.2 [M+H]⁺. The reaction mixture wasconcentrated to dryness and used as is in the next step.

Part 2, Step A: A mixture of crude boronic pinacol ester/boronic acidfrom Part 1 (˜4 g, ˜4 mmol),2-chloro-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one (0.792 g, 4.0 mmol,prepared in Example 14, Part 1), Pd(dppf)Cl₂.CH₂Cl₂ (146 mg, 0.20 mmol),K₂CO₃ (2M, 6.0 mL, 12.0 mmol), and CH₃CN (12 mL) was degassed and thenheated under N₂ at 60° C. for 2.5 hours. The volatiles were removed andthe residue was washed with water and CH₃CN to give7-fluoro-2-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-oneas a grayish solid (1.119 g, 89%). MS m/z 314.2 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.88-9.01 (1H, m), 8.39-8.48 (1H, m), 8.11-8.20 (2H, m),7.86-7.96 (1H, m), 7.21-7.29 (1H, m), 2.69 (3H, s).

Part 2, Step B: A mixture of7-fluoro-2-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one(63 mg, 0.2 mmol) and (S)-2-methylpiperazine (30 mg, 0.3 mmol) in DMA(0.5 mL) was heated at 120° C. for 15 hours. The volatiles were removedand the residue was chromatographed (10-15% MeOH in CH₂Cl₂) to give thetitle compound as a yellow solid (26 mg, 33%). M.P. 207-209° C.; MS m/z394.3 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 8.39 (1H, d, J=1.3 Hz),8.20-8.24 (1H, m), 8.05-8.16 (2H, m), 7.71-7.77 (1H, m), 7.11 (1H, s),3.56-3.68 (2H, m), 2.98-3.06 (1H, m), 2.78-2.88 (2H, m), 2.68 (3H, s),2.62-2.68 (1H, m), 2.27-2.34 (1H, m), 1.06 (3H, d, J=6.3 Hz).

As shown in Table 1 below, additional compounds disclosed herein may beprepared according to Example 36 by substituting the appropriatestarting materials, reagents and reaction conditions.

Example 37 Preparation of Cpd 443

Step A: A mixture of7-bromo-2-(3,4-dimethoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one (516 mg,2.0 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(740 mg, 2.4 mmol), potassium carbonate (828 mg, 6.0 mmol) andPd(dppf)Cl₂ (144 mg, 0.2 mmol) in acetonitrile (4 mL) was degassed andthen heated under N₂ at 60° C. overnight. The volatiles were removed andthe residue was chromatographed (30% EtOAc/CH₂Cl₂) to give tert-butyl4-(2-(3,4-dimethoxyphenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylateas a yellow solid (579 mg, 80%). MS m/z 362.8 [M+H]⁺.

Step B: To the product from Step A (400 mg, 1.1 mmol) was added1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole(220 mg, 1.2 mmol), Pd(dppf)Cl₂ (40 mg, 0.05 mmol), potassium carbonate(455 mg, 3.3 mmol) and CH₃CN (2 mL). The mixture was degassed and thenheated at 75° C. overnight. The mixture was washed with water and CH₃CN.The volatiles were removed and the residue was chromatographed with 0-2%MeOH in CH₂Cl₂ to give tert-butyl4-(2-(1-methyl-1H-indazol-5-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylateas an off-white solid (327 mg, 65%). MS m/z 458.5

Step C: Following the procedure in Example 22, Step D, the above productfrom Step B (327 mg, 0.72 mmol) and HCl in dioxane (4 M, 5 mL) providedthe title compound as an off-white solid (194 mg, 76%). M.P. 200-203°C.; MS m/z 358.2 [M+H]⁺; ¹H NMR (DMSO-d₆, 500 MHz) δ 8.80 (d, J=1.6 Hz,1H), 8.72 (d, J=1.6 Hz, 1H), 8.30-8.26 (m, 2H), 8.22 (d, J=1.6 Hz, 1H),7.77 (d, J=1.6 Hz, 2H), 7.09 (s, 1H), 6.62 (s, 1H), 4.11 (s, 3H),3.46-3.44 (m, 2H), 2.98-2.96 (m, 2H), 2.43-2.39 (m, 2H).

As shown in Table 1 below, additional compounds disclosed herein may beprepared according to Example 37 by substituting the appropriatestarting materials, reagents and reaction conditions.

Example 38 Preparation of Cpd 342

Step A: Following the procedure in Example 9, Step G,2-amino-5-bromo-pyridine (415 mg, 2.4 mmol), ethyl3-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-3-oxopropanoate (520 mg, 2.0mmol) and PPTs (25 mg, 0.1 mmol) gave2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-bromo-4H-pyrido[1,2-a]pyrimidin-4-oneas a yellow solid (498 mg, 67%). MS m/z 370.2 [M+H]⁺, 372.2 [M+2+H]⁺; ¹HNMR (500 MHz, DMSO-d₆) δ 8.99-9.09 (1H, m), 8.53-8.62 (1H, m), 8.08-8.18(1H, m), 7.68-7.75 (1H, m), 7.55-7.63 (1H, m), 7.01-7.09 (1H, m), 2.74(3H, s), 2.44 (3H, s).

Step B: Following the procedure in Example 22, Step C,7-bromo-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one(498 mg, 1.3 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(482 mg, 1.56 mmol), potassium carbonate (538 mg, 3.9 mmol) andPd(dppf)Cl₂ (95 mg, 0.13 mmol) in acetonitrile (3 mL) gave tert-butyl4-(2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylateas an off-white solid (0.57 g, 84%). MS m/z 473.5 [M+H]⁺; ¹H NMR (500MHz, DMSO-d₆) δ 8.80-8.89 (1H, m), 8.53-8.61 (1H, m), 8.23-8.32 (1H, m),7.71-7.79 (1H, m), 7.55-7.61 (1H, m), 6.99-7.04 (1H, m), 4.03-4.14 (2H,m), 3.55-3.65 (2H, m), 2.74 (3H, s), 2.53-2.58 (2H, m), 2.43 (3H, s),1.44 (9H, s).

Step C: Following the procedure in example 22, Step D, tert-butyl4-(2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylate,HCl (2 mL, 4N in dioxane) in CH₂Cl₂ (4 mL) gave the title compound as anoff-white solid (234 mg, 84%). M.P. 207-210° C.; MS m/z 373.4 [M+H]⁺; ¹HNMR (500 MHz, DMSO-d₆) δ 8.80 (1H, s), 8.55-8.60 (1H, m), 8.27-8.32 (1H,m), 7.73-7.78 (1H, m), 7.58-7.63 (1H, m), 7.00-7.05 (1H, m), 6.57-6.65(1H, m), 3.42-3.47 (2H, m), 2.93-2.98 (2H, m), 2.72-2.76 (2H, m), 2.44(3H, s), 2.39 (3H, s).

As shown in Table 1 below, additional compounds disclosed herein may beprepared according to Example 38 by substituting the appropriatestarting materials, reagents and reaction conditions.

Example 39 Preparation of Cpd 629

A mixture of(R)-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(3-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one(48 mg, 0.12 mmol, prepared according to Example 9), formaldehyde (0.039ml, 0.48 mmol, 37% in water) and sodium triacetoxyborohydride (51 mg,0.24 mmol) was stirred in dichloromethane (1 mL) for 1 hour. Thereaction mixture was diluted with dichloromethane and neutralized withsodium bicarbonate. The organics were dried, concentrated andchromatographed with 0-5% MeOH/CH₂Cl₂ to provide the title compound as ayellow solid (45 mg, 90%). M.P. 257-259° C.; MS m/z 418.5 [M+H]⁺; ¹H NMR(500 MHz, DMSO-d₆) δ 8.56 (1H, s), 8.25-8.26 (1H, m), 8.12-8.14 (1H, m),7.72-7.74 (1H, m), 7.55 (1H, s), 6.95 (1H, s), 3.60-3.65 (2H, m), 3.08(2H, q, J=7.6 Hz), 2.84-2.89 (2H, m), 2.43-2.52 (2H, m, obscured byDMSO-d₆), 2.45 (3H, s), 2.29-2.31 (1H, m), 2.24 (3H, s), 1.33 (3H, t,J=7.6 Hz), 1.91 (3H, d, J=6.2 Hz).

As shown in Table 1 below, additional compounds disclosed herein may beprepared according to Example 39 by substituting the appropriatestarting materials, reagents and reaction conditions.

Example 40 Preparation of Cpd 625 and Cpd 626

Step A: A mixture of ethyl4-chloro-6-methylpyrazolo[1,5-a]pyrazine-2-carboxylate (2.39 g, 10 mmol,prepared in Example 9, Step C) and sodium methoxide (60 mL, 30 mmol, 0.5M in MeOH) was stirred at 30° C. for 1 hour. The mixture wasconcentrated to remove most of the methanol, diluted with water andneutralized with 6 N HCl. A white solid precipitated out and wasfiltered, washed with water and CH₃CN, and dried to give ethyl4-methoxy-6-methylpyrazolo[1,5-a]pyrazine-2-carboxylate as a white solid(1.387 g, 62%). MS m/z 222.2 [M-CH₃+H].

Step B: Following the procedure in Example 9, Step E, tert-butyl acetate(1.6 mL, 12.3 mmol), LDA (10.2 mL, 15.4 mmol, 1.5 M in THF) and ethyl4-methoxy-6-methylpyrazolo[1,5-a]pyrazine-2-carboxylate (1.387 g, 6.2mmol) gave tert-butyl3-(4-methoxy-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-3-oxopropanoate as anoil (1.35 g, 72%). MS m/z 306.3 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 8.35(1H, s), 7.27 (1H, s) 4.05 (3H, s), 4.01 (2H, s), 2.36 (3H, s), 1.38(9H, s).

Step C: Following the procedure in Example 9, Step F, tert-butyl3-(4-methoxy-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-3-oxopropanoate (1.35g, 4.43 mmol) and EtOH (10 mL) gave ethyl3-(4-methoxy-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-3-oxopropanoate as ayellowish solid, which was used directly in the next step withoutfurther purification. MS m/z 278.3 [M+H]⁺.

Step D: A mixture of ethyl3-(4-methoxy-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-3-oxopropanoate (˜4.43mmol), 2-amino-5-fluoro-pyridine (0.596 g, 5.3 mmol), PPTs (100 mg, 0.4mmol) and tetraethyl orthosilicate (1.0 mL, 4.43 mmol) in m-xylene (2.2mL) was heated at 130° C. After 15 hours, the mixture was cooled to roomtemperature and washed with CH₂Cl₂ to give7-fluoro-2-(4-methoxy-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-oneas a yellow solid (1.015 g, 70%). MS m/z 326.3 [M+H]⁺.

Step E: A mixture of7-fluoro-2-(4-methoxy-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one(98 mg, 0.30 mmol) and N-methyl-piperazine (150 mg, 1.5 mmol) in DMA(0.6 mL) was heated at 130° C. After 6 hours, the mixture was cooled toroom temperature and chromatographed with 5% MeOH/CH₂Cl₂ and 10% 3.5 NNH₃ in MeOH/CH₂Cl₂ to give Cpd 625 (12 mg, 10%) and Cpd 626 (8.5 mg,7%), each as yellow solids.

Cpd 625: M.P. 242-244° C.; MS m/z 406.5 [M+H]⁺; ¹H NMR (500 MHz,DMSO-d₆) δ 8.33-8.38 (1H, m), 8.24-8.30 (1H, m), 8.09-8.15 (1H, m),7.70-7.74 (1H, m), 7.34-7.39 (1H, m), 6.92-6.96 (1H, m), 4.07 (3H, s),3.21-3.29 (4H, m), 2.5 (4H, m, obscured by DMSO-d₆), 2.37 (3H, s), 2.26(3H, s).

Cpd 626: M.P. 280-283° C.; MS m/z 392.4 [M+H]⁺; ¹H NMR (500 MHz,DMSO-d₆) δ 11.4 (1H, s), 8.24-8.28 (1H, m), 8.09-8.14 (1H, m), 7.70-7.75(1H, m), 7.63-7.67 (1H, m), 7.48 (1H, s), 6.88 (1H, s), 3.22-3.29 (4H,m), 2.51-2.56 (4H, m), 2.24-2.30 (3H, s), 2.15 (3H, s).

Example 41 Preparation of Cpd 688

Step A: A mixture of ethyl4-chloro-6-methylpyrazolo[1,5-a]pyrazine-2-carboxylate (0.956 g, 4 mmol,prepared in Example 9, Step C), dimethylamine (2.1 mL, 4.2 mmol, 2.0 Min THF) and Et₃N (0.84 mL, 6.0 mmol) was heated at 60° C. After 15hours, the mixture was concentrated, the residue was dissolved in EtOAc,washed with water, dried and concentrated to give ethyl4-(dimethylamino)-6-methylpyrazolo[1,5-a]pyrazine-2-carboxylate as anoff-white solid (0.99 g, 99%). MS m/z 249.3 [M+H]⁺.

Step B: To a solution of ethyl4-(dimethylamino)-6-methylpyrazolo[1,5-a]pyrazine-2-carboxylate (0.99 g,4.0 mmol) and EtOAc (1.95 mL, 20 mmol) in THF (30 mL) at −20° C. wasadded LiHMDS (11.1 mL, 10 mmol, 0.9 M in THF). After 1 hours, themixture was quenched with saturated NH₄Cl, extracted with EtOAc. Theorganics were concentrated and chromatographed with 2% MeOH/DCM to giveethyl3-(4-(dimethylamino)-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-3-oxopropanoateas a pale yellow oil (0.48 g, 40%). MS m/z 291.3 [M+H]⁺; ¹H NMR (500MHz, DMSO-d₆) δ 7.73 (1H, s), 7.05 (1H, s), 5.43 (2H, s), 3.96 (2H, q,J=7.0 Hz), 3.28 (6H, s), 2.20 (3H, s), 1.16 (3H, t, J=7.0 Hz)

Step C: Following the procedure in Example 40, Step D, ethyl3-(4-(dimethylamino)-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-3-oxopropanoate(0.48 g, 1.6 mmol), 2-amino-5-fluoro-pyridine (179 mg, 1.6 mmol), PPTs(40 mg, 0.16 mmol) and tetraethyl orthosilicate (0.36 mL, 1.6 mmol) inm-xylene (0.8 mL) gave2-(4-(dimethylamino)-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-oneas a yellow solid (0.39 g, 72%). MS m/z 339.2 [M+H]⁺; ¹H NMR (500 MHz,DMSO-d₆) δ 8.92-9.00 (1H, m), 8.06-8.18 (1H, m), 7.91-7.94 (1H, m),7.85-7.91 (1H, m), 7.55-7.61 (1H, m), 6.98-7.08 (1H, m), 3.36 (6H, s),2.25 (3H, s).

Step D: A mixture of7-fluoro-2-(4-methoxy-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one(50 mg, 0.15 mmol) and piperazine (86 mg, 1.0 mmol) in DMA (0.5 mL) washeated at 150° C. After 2 hours, the mixture was cooled to roomtemperature and washed with CH₃CN to give the title compound as a yellowsolid (60 mg, 98%). M.P. 245-248° C.; MS m/z 405.4 [M+H]⁺; ¹H NMR (500MHz, DMSO-d₆) δ 8.23-8.28 (1H, m), 8.06-8.11 (1H, m), 7.89-7.92 (1H, m),7.69-7.75 (1H, m), 7.50-7.55 (1H, m), 6.92 (1H, s), 3.35 (6H, s),3.12-3.19 (4H, m), 2.87-2.92 (4H, m), 2.80 (1H, s), 2.24 (3H, s).

Example 42 Preparation of Cpd 694

Step A: To a mixture of2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one(78 mg, 0.2 mmol, prepared according to the procedure in Examples 38 and24) and 2,2-dimethyl-1,3-dioxan-5-one (72 mg, 0.5 mmol, 90% tech grade)in dichloroethane (1 mL) were added NaBH(OAc)₃ (106 mg, 0.5 mmol) and 1drop of AcOH. The mixture was stirred at 60° C. After 1 hour, themixture was quenched with saturated NaHCO₃, extracted with CH₂Cl₂,concentrated and chromatographed (2-5% MeOH/CH₂Cl₂) to give7-(1-(2,2-dimethyl-1,3-dioxan-5-yl)piperidin-4-yl)-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-oneas a white solid (70 mg, 70%). MS m/z 503.5 [M+H]⁺; ¹H NMR (500 MHz,DMSO-d₆) δ 8.75-8.82 (1H, m), 8.54-8.61 (1H, m), 8.00-8.10 (1H, m),7.72-7.79 (1H, m), 7.58-7.63 (1H, m), 6.99-7.03 (1H, m), 3.86-3.95 (2H,m), 3.71-3.81 (2H, m), 3.06-3.15 (2H, m), 3.00-3.06 (2H, m), 2.70-2.80(1H, m), 2.53-2.59 (1H, m), 2.45 (3H, s), 2.28-2.38 (2H, m), 1.82-1.90(2H, m), 1.59-1.71 (2H, m), 1.32-1.37 (6H, m), 1.27 (3H, s).

Step B: To a mixture of7-(1-(2,2-dimethyl-1,3-dioxan-5-yl)piperidin-4-yl)-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one(50 mg, 0.1 mmol) in THF (10 mL) was added HCl (1.3 mL, 2.6 mmol, 2 N).The mixture was stirred at room temperature. After 15 hours, the mixturewas treated with excess of 7N NH₃ in MeOH, concentrated andchromatographed (10% 2.5 N NH₃ in MeOH/CH₂Cl₂) to give the titlecompound as a yellow solid (45 mg, 97%). M.P. 228-230° C.; MS m/z 463.6[M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 8.77-8.84 (1H, m), 8.54-8.61 (1H,m), 8.02-8.10 (1H, m), 7.90-7.94 (1H, m), 7.74-7.79 (1H, m), 7.57-7.63(1H, m), 6.99-7.05 (1H, m), 4.21-4.31 (2H, m), 3.42-3.59 (4H, m), 3.10(2H, q, J=7.5 Hz), 2.89-3.00 (2H, m), 2.70-2.72 (1H, m), 2.57-2.62 (1H,m), 2.45 (3H, s), 1.79-1.89 (2H, m), 1.63-1.75 (2H, m), 1.34 (3H, t,J=7.5 Hz).

Example 43 Preparation of Cpd 662

A mixture of2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one(56 mg, 0.15 mmol, prepared according to the procedure in Example 24),1-bromo-2-fluoroethane (23 mg, 0.18 mmol) and K₂CO₃ (23 mg, 0.18 mmol)in DMF (1 mL) was heated at 80° C. After 7 hours, the mixture was cooledto room temperature and chromatographed (5% MeOH/CH₂Cl₂) to give thetitle compound as a yellow solid (29 mg, 44%). M.P. 197-199° C.; MS m/z421.4 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 8.79-8.85 (1H, m), 8.55-8.60(1H, m), 8.05-8.11 (1H, m), 7.73-7.80 (1H, m), 7.57-7.62 (1H, m), 7.02(1H, s), 4.59-4.65 (1H, m), 4.48-4.55 (1H, m), 3.01-3.07 (2H, m),2.69-2.75 (1H, m), 2.74 (3H, s), 2.68-2.72 (1H, m), 2.62-2.67 (1H, m),2.43 (3H, s), 2.12-2.21 (2H, m), 1.85-1.88 (2H, m), 1.70-1.88 (2H, m).

As shown in Table 1 below, additional compounds disclosed herein may beprepared according to Example 43 by substituting the appropriatestarting materials, reagents and reaction conditions.

Example 44 Preparation of Cpd 798

Part 1, Step A: To a solution of 2,6-dimethylpiperidin-4-one (1.27 g, 10mmol, a mixture of trans/cis isomers in a ratio of ˜1.5/1) anddi-tert-butyl dicarbonate (2.40 g, 11 mmol) in ether was added NaOH (11mL, 11 mmol, 1 N in water). The mixture was stirred at room temperature.After 36 hours, the mixture was extracted with ether. The organics wereconcentrated and chromatographed (5-30% EtOAc/Hexanes) to give a mixtureof tert-butyl 2,6-dimethyl-4-oxopiperidine-1-carboxylate as a Tran/cismixture in a ratio of ˜1.2/1 (1.99 g, 87%, clear oil). Upon standingovernight, a solid precipitated from the oil, which was filtered andwashed with ether to give the tert-butyltrans-2,6-dimethyl-4-oxopiperidine-1-carboxylate (0.376 g, 16%)(95%trans by ¹H NMR). ¹H NMR (500 MHz, CDCl₃) δ 4.33-4.45 (2H, m), 2.80-2.90(2H, m), 2.33-2.44 (2H, m), 1.50 (9H, s), 1.26 (6H, d, J=6.9 Hz). The ¹HNMR is consistent with that of the trans-isomer in a mixture of cis andtrans-isomers (US200839454, JOC, 1993, 58, 1109-1117).

Part 1, Step B: To a solution of the tert-butyltrans-2,6-dimethyl-4-oxopiperidine-1-carboxylate (266 mg, 1.17 mmol) inTHF (7 mL) at −78° C. was added NaHMDS. After 1 hour,N-Phenyl-bis(trifluoromethanesulfonimide) (0.50 g, 1.4 mmol) in THF (3mL) was added. The reaction mixture was stirred at room temperature for2 hours, quenched with saturated NH₄Cl and extracted with ether. Theorganics were concentrated and chromatographed with 1% EtOAc/Hexanes togivetert-butyl-trans-2,6-dimethyl-4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate(0.415 g, 98%). ¹H NMR (500 MHz, CDCl₃) δ 5.77-5.85 (1H, m), 4.29-4.44(2H, m), 2.81-2.90 (1H, m), 2.15-2.23 (1H, m), 1.48 (9H, s), 1.37 (3H,d, J=6.6 Hz), 1.24 (3H, d, J=6.6 Hz).

Part 2, Step A: Following the procedure of Example 14, Part 2,7-bromo-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one(0.74 g, 2.0 mmol, prepared in Example 38, Step A), KOAc (590 mg, 6.0mmol), bis(pincolato)diboron (560 mg, 2.2 mmol), and Pd(dppf)Cl₂.CH₂Cl₂(82 mg, 0.1 mmol) in dioxane (6 mL) provided2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-ylboronicacid. The crude intermediate was used directly in the next step. MS m/z336.3 [M+H]⁺.

Part 2, Step B: Following the procedure of Example 14, Part 3, Step A,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-ylboronicacid (˜2 mmol),tert-butyl-trans-2,6-dimethyl-4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate(0.415 g, 1.15 mmol), potassium carbonate (3.5 mL, 2.0M) andPd(dppf)Cl₂.CH₂Cl₂ (82 mg, 0.1 mmol) in acetonitrile (10 mL) providedtert-butyl4-(2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)-trans-2,6-dimethyl-5,6-dihydropyridine-1(2H)-carboxylateas a yellow solid (0.5 g, 87%). MS m/z 501.4 [M+H]⁺.

Part 2, Step C: Following the procedure in Example 38, Step C,tert-butyl4-(2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)-trans-2,6-dimethyl-5,6-dihydropyridine-1(2H)-carboxylate(50 mg, 0.1 mmol) and HCl in dioxane (4 M, 0.5 mL) provided the titlecompound as a yellow solid (25 mg, 62%). M.P. 228-231° C.; MS m/z 401.3[M+H]⁺; ¹HNMR (500 MHz, DMSO-d₆) δ 8.77-8.82 (1H, m), 8.54-8.58 (1H, m),8.25-8.32 (1H, m), 7.70-7.76 (1H, m), 7.57 (1H, s), 7.02 (1H, s),6.50-6.58 (1H, m), 3.64-3.75 (1H, m), 3.08-3.18 (1H, m), 2.73 (3H, s),2.41-2.44 (1H, m), 2.43 (3H, s), 1.99-2.08 (1H, m), 1.21 (3H, d, J=6.6Hz), 1.16 (3H, d, J=6.3 Hz).

Example 45 Preparation of Cpd 764

Step A: Following the procedure in Example 9, Step H,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one(618 mg, 2.0 mmol), (R)-tert-butyl pyrrolidin-3-ylmethylcarbamate (481mg, 2.4 mmol) and DMA (2.0 mL) provided (S)-tert-butyl(1-(2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)pyrrolidin-3-yl)methylcarbamate(0.90 g, 92%) as a yellow solid. MS m/z 490.5 [M+H]⁺; ¹H NMR (500 MHz,DMSO-d₆) δ 8.50-8.59 (1H, m), 7.97-8.03 (1H, m), 7.72-7.82 (2H, m),7.48-7.57 (1H, m), 7.04-7.08 (1H, m), 6.87-6.94 (1H, m), 3.41-3.50 (2H,m), 3.35-3.41 (1H, m), 2.97-3.16 (3H, m), 2.73 (3H, s), 2.47-2.51 (1H,m, obscured by DMSO-d₆), 2.43 (3H, s), 2.04-2.16 (1H, m), 1.71-1.83 (1H,m), 1.39 (9H, s).

Step B: Following the procedure in Example 38, Step C, (S)-tert-butyl(1-(2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)pyrrolidin-3-yl)methylcarbamate(0.39 g, 0.8 mmol), HCl (2.0 mL, 4 M in dioxane) and CH₂Cl₂ (10 mL)provided the title compound as a yellow solid (0.19 g, 62%). M.P.244-246° C.; MS m/z 390.4 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 8.52-8.57(1H, m), 7.96-8.03 (1H, m), 7.73-7.80 (2H, m), 7.52 (1H, s), 6.90 (1H,s), 3.42-3.50 (2H, m), 3.34-3.41 (1H, m), 3.10-3.18 (1H, m), 2.73 (3H,s), 2.59-2.70 (2H, m), 2.43 (3H, s), 2.34-2.42 (1H, m), 2.09-2.16 (1H,m), 1.73-1.82 (1H, m).

As shown in Table 1 below, additional compounds disclosed herein may beprepared according to Example 45 by substituting the appropriatestarting materials, reagents and reaction conditions.

Example 46 Preparation of Cpd 294

Step A:2-chloro-7-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one(182 mg, 0.6 mmol), prepared according to Example 30, Step A, wascombined with tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(222 mg, 0.72 mmol), tetrakis(triphenylphosphine) palladium(0) (67 mg,0.06 mmol), CH₃CN (2 mL) and aqueous K₂CO₃ (1 M, 2 mL). The mixture washeated at 80° C. for 18 hours. After cooling to room temperature, themixture was filtered, providing tert-butyl4-(7-(3-fluoro-4-methoxyphenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylateas a crude product that was used directly in the next step.

Step B: The tert-butyl4-(7-(3-fluoro-4-methoxyphenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylatefrom step A was dissolved in TFA (2 mL). After 10 minutes, volatileswere removed with a nitrogen stream. The residue was partitioned inCH₂Cl₂ and aqueous K₂CO₃ (1 M). The organic layer was loaded onto silicagel, eluting with 0-10% MeOH (3% NH₃) in CH₂Cl₂, affording the titlecompound as a white powder (150 mg, 72%). M.P. 188-192° C.; MS m/z 352.1[M+H]⁺; ¹H NMR (DMSO-d₆, 500 MHz): δ 9.05 (1H, d, J=2.3 Hz), 8.28 (1H,dd, J=9.4 Hz, 2.2 Hz), 7.76 (1H, dd, J=12.7 Hz, 2.3 Hz), 7.70 (1H, d,J=9.3 Hz), 7.63 (1H, m), 7.33 (1H, t, J=8.8 Hz), 7.14 (1H, m), 6.44 (1H,s), 3.92 (3H, s), 3.46 (2H, m), 2.91 (2H, m), 2.39 (2H, m).

As shown in Table 1 below, additional compounds disclosed herein may beprepared according to Example 46 by substituting the appropriatestarting materials, reagents and reaction conditions.

Example 47 Preparation of Cpd 714

Step A: 3-Bromo-2-nitropyridine (2.0 g, 10 mmol) was dissolved in THF(20 mL). 2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (205 mg, 0.5mmol) and palladium(II) acetate (113 mg, 0.5 mmol) were added to themixture. To the mixture was added cyclopropylzinc bromide (15 mmol, 0.5M in THF). The mixture was stirred at room temperature for 3 hours. Themixture was concentrated and chromatographed on silica gel, eluting with0-5% EtOAc in CH₂Cl₂ to provide 3-cyclopropyl-2-nitropyridine (1.1 g,67%) as a white solid. MS m/z 165.2 [M+H]⁺.

Step B: 3-Cyclopropyl-2-nitropyridine (1.1 g, 6.7 mmol) was dissolved inMeOH (150 mL). The solution was passed over a cartridge containing 10%Pd/C under H2 (30 bar) at 30° C. The solution was concentrated leaving3-cyclopropyl-2-aminopyridine (898 mg, quant.) as colorless oil. MS m/z135.1 [M+H]⁺.

Step C: Following the procedure in Example 16, Step A,3-cyclopropyl-2-aminopyridine (898 mg, 6.7 mmol), N-bromosuccinimide(1.3 g, 7.4 mmol), CH₃CN (15 mL) and chloroacetone (0.81 mL, 10 mmol)provided 6-bromo-8-cyclopropyl-2-methylimidazo[1,2-a]pyridine as a tanpowder (255 mg, 15%). MS m/z 251.1 [M+H]⁺, 253.1 [M+2+H]⁺.

Step D: Following the procedure in Example 14, Part 2,6-Bromo-8-fluoro-2-methylimidazo[1,2-a]pyridine (255 mg, 1.0 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (380 mg, 1.5mmol), [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (41mg, 0.05 mmol) and potassium acetate (196 mg, 2 mmol) provided8-cyclopropyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine.The crude product was used directly in the next step.

Step E: Following the procedure in Example 14, Part 3, Step A, the crudeproduct of8-cyclopropyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridinefrom Step D and 2-chloro-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one (1mmol, prepared in Example 14, Part 1, Step B),tetrakis(triphenylphosphine) palladium(0) (112 mg, 0.1 mmol), CH₃CN (4mL) and aqueous K₂CO₃ (1M, 4 mL) provided2-(8-cyclopropyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-oneas a tan powder (330 mg, 99%). MS m/z 335.2 [M+H]⁺.

Step F: Following the procedure in Example 14, Part 3, Step B,2-(8-cyclopropyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one(50 mg, 0.15 mmol) and piperazine (65 mg, 0.75 mmol) afforded the titlecompound as a tan powder (38 mg, 63%). M.P. 274-277° C.; MS m/z 401.4[M+H]⁺; ¹H NMR (DMSO-d₆, 500 MHz): δ 9.14 (1H, d, J=1.7 Hz), 8.21 (1H,d, J=2.9 Hz), 8.07 (1H, dd, J=9.7 Hz, 2.8 Hz), 7.79 (1H, d, J=1.0 Hz),7.67 (1H, d, J=9.2 Hz), 7.43 (1H, m), 6.99 (1H, s), 3.14 (4H, m), 2.89(4H, m), 2.48 (1H, m), 2.37 (3H, s), 2.35 (1H, br s), 1.13 (2H, m), 1.04(2H, m).

As shown in Table 1 below, additional compounds disclosed herein may beprepared according to Example 47 by substituting the appropriatestarting materials, reagents and reaction conditions.

Example 48 Preparation of Cpd 674

Step A: 2-Aminonicotinic acid (4.8 g, 35 mmol) was suspended in THF (100mL). To the mixture was added borane THF complex (40 mmol, 1 M in THF).The mixture was stirred at room temperature for 18 hours. The excessreagent was quenched by the addition of aqueous potassium hydroxide (2M, 15 mL). The mixture was stirred vigorously for 10 minutes. Theorganic layer was collected and concentrated. The residue waschromatographed on silica gel, eluting with 0-10% MeOH in CH₂Cl₂ toprovide (2-aminopyridin-3-yl)methanol (1.0 g, 23%) as a white solid. MSm/z 125.1 [M+H]⁺.

Step B: Following the procedure in Example 16, Step A,(2-aminopyridin-3-yl)methanol (1.0 g, 8 mmol), N-bromosuccinimide (1.57g, 8.8 mmol), CH₃CN (16 mL) and chloroacetone (0.81 mL, 10 mmol)provided (6-bromo-2-methylimidazo[1,2-a]pyridin-8-yl)methanol as a tanpowder (82 mg, 4%). MS m/z 241.1 [M+H]⁺, 243.1 [M+2+H]⁺.

Step C: Following the procedure in Example 14, Part 2,6-Bromo-8-fluoro-2-methylimidazo[1,2-a]pyridine (85 mg, 0.35 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (133 mg,0.53 mmol), [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)(30 mg, 0.035 mmol) and potassium acetate (69 mg, 0.7 mmol) provided(2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridin-8-yl)methanol.The crude product was used directly in the next step.

Step D: Following the procedure in Example 14, Part 3, Step A, the crudeproduct of(2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridin-8-yl)methanolfrom Step C and 2-chloro-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one (0.35mmol, prepared in Example 14, Part 1, Step B,tetrakis(triphenylphosphine) palladium(0) (39 mg, 0.035 mmol), CH₃CN (2mL) and aqueous K₂CO₃ (1 M, 2 mL) provided7-fluoro-2-(8-(hydroxymethyl)-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-oneas a tan powder (100 mg, 88%). MS m/z 325.2 [M+H]⁺.

Step E: Following the procedure in Example 14, Part 3, Step B,7-fluoro-2-(8-(hydroxymethyl)-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one(120 mg, 0.15 mmol) and piperazine (65 mg, 0.75 mmol) afforded the titlecompound as a tan powder (120 mg, 99%). M.P.>320° C.; MS m/z 391.3[M+H]⁺; ¹H NMR (DMSO-d₆, 500 MHz): δ 9.23 (1H, s), 8.24 (1H, d, J=2.6Hz), 8.07 (1H, dd, J=9.7 Hz, 2.6 Hz), 7.96 (1H, s), 7.79 (1H, s), 7.73(1H, d, J=6.7 Hz), 6.87 (1H, s), 4.86 (2H, s), 3.14 (4H, m), 2.89 (4H,m), 2.37 (3H, s).

Example 49 Preparation of Cpd 353

Step A: Ethyl 3-(3,4-dimethoxyphenyl)-3-oxopropanoate (907 mg, 3.6 mmol)was dissolved in methanol (2 mL). p-Toluenesulfonic acid monohydrate(34.2 mg, 0.18 mmol) was added to the solution, followed bytrimethylorthoformate (0.59 mL, 5.4 mmol). The solution was stirred at80° C. for 1 hour. Volatiles were removed with a stream of nitrogen. Tothe crude material were added 5-bromopyrimidin-2-amine (550 mg, 3.1mmol) and diphenyl ether (2 mL). The mixture was heated at 170° C. for10 minutes. The reaction mixture was passed through a through a flashsilica column (33% Hexanes/CH₂Cl₂) to giveethyl-3-(-5-bromopyrimidin-2(1H)-ylideneamino)-3-(3,4-dimethoxyphenyl)acrylateas a yellow solid. MS m/z 408.0 [M+H]⁺, 410.0 [M+2+H]⁺.

Step B: Toethyl-3-(-5-bromopyrimidin-2(1H)-ylideneamino)-3-(3,4-dimethoxyphenyl)acrylatewas added diphenyl ether (2 mL). The reaction was heated to 220° C. for1.5 hours. The mixture was purified by chromatography (100% CH₂Cl₂) toprovide7-bromo-2-(3,4-dimethoxyphenyl)-4H-pyrimido[1,2-a]pyrimidin-4-one (314mg, 28% for 2 steps) as a yellow solid. MS m/z 361.9 [M+H]⁺, 363.9[M+2+H]⁺; ¹H NMR (500 MHz, DMSO-d₆): δ 9.30 (1H, d, J=2.7 Hz), 9.20 (1H,d, J=2.9 Hz), 7.88 (1H, dd, J=8.5 Hz, 2.6 Hz), 7.79 (1H, d, J=2.2 Hz),7.15 (1H, s), 7.11 (1H, d, J=8.5 Hz), 3.88 (3H, s), 3.85 (3H, s).

Step C: A mixture of7-bromo-2-(3,4-dimethoxyphenyl)-4H-pyrimido[1,2-a]pyrimidin-4-one (53.7mg, 0.15 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(50.5 mg, 0.016 mmol), Pd(dppf)Cl₂ (11 mg, 0.015 mmol), K₂CO₃ (62.2 mg,0.45 mmol), and ACN (1 mL) was degassed and then heated under N₂ at 80°C. overnight. The volatiles were removed and the residue was used in thenext step without purification. MS m/z 465.4 [M+H]⁺.

Step D: A solution of tert-butyl4-(2-(3,4-dimethoxyphenyl)-4-oxo-4H-pyrimido[1,2-a]pyrimidin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylatein CH₂Cl₂/TFA (0.5 mL/0.5 mL) was stirred at 0° C. for 2 hours. Aftermost of the TFA and CH₂Cl₂ were removed by rotary evaporation, ice-coldsaturated NaHCO₃ was added to the reaction mixture. The mixture wasextracted with CH₂Cl₂. The organic layer was dried over MgSO₄,concentrated, and chromatographed (5% MeOH/CH₂Cl₂) to provide the titlecompound as a yellow solid. MS m/z 365.1 [M+H⁺].

Example 50 Preparation of Cpd 486

Step A: A mixture of 2-chloro-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one(995 mg, 5 mmol, prepared in Example 14, Part 1), CuI (19.0 mg, 0.1mmol), PdCl₂(PPh₃)₂ (70.2 mg, 0.1 mmol), ethynyltrimethylsilane (2.1 mL,15 mmol), triethylamine (2.1 mL, 15 mmol) in DMF (10 mL) was degassedand then heated under N₂ at 50° C. overnight. The volatiles were removedand the crude7-fluoro-2-((trimethylsilyl)ethynyl)-4H-pyrido[1,2-a]pyrimidin-4-one wasused directly for the next step. MS m/z 261.1 [M+H⁺].

Step B: Potassium carbonate (1.0 g, 7.5 mmol) was added to the solutionof crude7-fluoro-2-((trimethylsilyl)ethynyl)-4H-pyrido[1,2-a]pyrimidin-4-one inMeOH (33 mL). The mixture was stirred at 0° C. for 0.5 hours. After MeOHwas removed by rotary evaporation, water was added. The precipitate wasfiltered and purified by silica chromatography (8% EtOAc/CH₂Cl₂) to give2-ethynyl-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one (192.1 mg, 20% for 2steps) as a yellow solid. MS m/z 189.1 [M+H⁺].

Step C: A mixture of 2-ethynyl-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one(192.1 mg, 1.0 mmol), 4-iodo-2,6-dimethylpyridin-3-ol (305.3 mg, 1.2mmol), CuI (9.7 mg, 0.05 mmol), PdCl₂(PPh₃)₂ (35.8 mg, 0.05 mmol),triethylamine (288 μL, 2 mmol) in DMF (1.7 mL) was degassed and thenheated under N₂ at 40° C. overnight. After most of the DMF was removed,water was added. The precipitate was filtered and purified bychromatography (14% EtOAC/CH₂Cl₂) to give2-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one(126.3 mg, 41%) as a yellow solid. MS m/z 310.1 [M+H⁺].

Step D: Piperazine (64.6 mg, 0.75 mmol) was added to a solution of2-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one(46.4 mg, 0.15 mmol) in DMA (0.5 mL). The reaction mixture was heated at120° C. for 2 hours. After most of the DMA was removed, CH₃CN was addedto the reaction mixture, and a precipitate was formed. The precipitatewas filtered, washed with water and dried to provide the title compoundas a yellow solid (30 mg, 53%). M.P. 198-200° C.; MS m/z 376.3 [M+H⁺];¹H NMR (500 MHz, DMSO-d₆): δ 8.25 (1H, d, J=2.5 Hz), 8.13 (1H, dd, J=9.9Hz, 2.5 Hz), 7.73 (1H, d, J=9.8 Hz), 7.64 (1H, s), 7.41 (1H, s), 6.94(1H, s), 3.17 (4H, m), 2.90 (4H, m), 2.71 (3H, s), 2.51 (3H, s), 2.07(1H, s).

As shown in Table 1 below, additional compounds disclosed herein may beprepared according to Example 50 by substituting the appropriatestarting materials, reagents and reaction conditions.

Example 51 Preparation of Cpd 603

Step A: A mixture of 5-bromopyridin-2-amine (433 mg, 2.5 mmol),tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(928 mg, 3.0 mmol), PdCl₂dppf (204 mg, 0.25 mmol), K₂CO₃ (1.04 g, 7.5mmol) in acetonitrile (8.0 mL) was degassed and then stirred at 80° C.overnight. The volatiles were removed and the residue waschromatographed with 7% MeOH in CH₂Cl₂ to provide tert-butyl4-(6-aminopyridin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate as a lightyellow oil (599 mg, 87%). MS m/z 276.3 [M+H]⁺.

Step B: A solution of the product from Step A (599 mg, 2.2 mmol) inmethanol (10 mL) was hydrogenated using Pd/C (10%, 60 mg) in a Parrshaker (60 psi) overnight. The mixture was filtered through Celite,evaporated and chromatographed with 7% MeOH in DCM to provide tert-butyl4-(6-aminopyridin-3-yl)piperidine-1-carboxylate as a brown oil (600 mg,99%). MS m/z 278.3 [M+H]⁺.

Step C: A mixture of the product from Step B (600 mg, 2.2 mmol) andbis(2,4,6-trichlorophenyl) malonate (1.0 g, 2.2 mmol) in THF (8.0 mL)was stirred at room temperature for 1 hour. The mixture was thenfiltered and the solid was washed with DCM. The cake was collected anddried to give tert-butyl4-(2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)piperidine-1-carboxylateas an off-white solid (455 mg, 63%). MS m/z 346.4 [M+H]⁺.

Step D: Into a solution of the product from Step C (455 mg, 1.3 mmol) inDMF (6 mL) at room temperature was added NaH (60%, 62 mg, 1.6 mmol). Themixture was stirred for 15 minutes, thenN-phenylbis(trifluoromethanesulfonimide) (511 mg, 1.4 mmol) was added inone portion. The mixture was stirred at room temperature overnight.Aqueous workup followed by purification with 3% MeOH in CH₂Cl₂ providedtert-butyl 4-(4-oxo-2-(trifluoromethylsulfonyloxy)-4H-pyrido[1,2-a]pyrimidin-7-yl)piperidine-1-carboxylate asan off-white solid (521 mg, 84%).

Step E: A mixture of the product from Step D (300 mg, 0.62 mmol),1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole(142 mg, 0.81 mmol), PdCl₂dppf (51 mg, 0.062 mmol), K₃PO₄ (193 mg, 0.93mmol) in dioxane (2.0 mL) was degassed and then stirred at 100° C.overnight. The volatiles were removed and the residue waschromatographed with 10% MeOH in CH₂Cl₂ to give tert-butyl4-(2-(1-methyl-1H-indazol-5-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)piperidine-1-carboxylatewith some impurities (˜300 mg), which was used directly in the nextstep. MS m/z 460.5 [M+H]⁺.

Step F: Following the procedure in Example 22, Step D, the above productfrom Step E (˜300 mg) and HCl in dioxane (4 M, 5 mL) provided the titlecompound as a white solid (196 mg, 88%, in two steps). M.P. 268-270° C.;MS m/z 360.4 [M+H]⁺; ¹H NMR (DMSO-d₆, 500 MHz) δ 8.75 (s, 1H), 8.70 (s,1H), 8.27 (dd, J=9.0 Hz, 1.6 Hz, 1H), 8.21 (s, 1H), 8.00 (dd, J=9 Hz,1.6 Hz, 1H), 7.76 (d, J=9 Hz, 2H), 7.06 (s, 1H), 4.10 (s, 3H), 3.06 (d,J=10 Hz, 2H), 2.84-2.79 (m, 1H), 2.64-2.59 (m, 2H), 2.04 (bs, 1H), 1.81(d, J=10 Hz, 2H), 1.56-1.53 (m, 2H).

As shown in Table 1 below, additional compounds disclosed herein may beprepared according to Example 51 by substituting the appropriatestarting materials, reagents and reaction conditions.

Example 52 Preparation of Cpd 769

Step A: To an oven dried, argon filled flask was added7-bromo-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one(270 mg, 0.73 mmol, prepared in Example 38, Step A), CuI (3.4 mg, 5%),PdCl₂(PPh₃)₂ (30 mg, 5%), triethylamine (1 mL) and DMF (1 mL). Theresulting mixture was purged with argon three times and then a solutionof tert-butyl prop-2-ynylcarbamate (0.14 g, 0.88 mmol) in DMF (1 mL) wasadded. The mixture was heated at 80° C. overnight, then cooled to roomtemperature. After addition of water, the resulting solids were filteredand washed with water and CH₃CN sequentially to provide tert-butyl3-(2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)prop-2-ynylcarbamate(260 mg, 80%). MS m/z 445.2 [M+H]⁺.

Step B: Following the procedure in Example 22, Step D, the above productfrom Step A (100 mg, 0.23 mmol) and HCl in dioxane (4 M, 3 mL) provided7-(3-aminoprop-1-ynyl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-oneas an off-white solid (50 mg, 66%). MS m/z 345.4 [M+H]⁺.

Step C: The above product from Step C (50 mg, 0.15 mmol) was mixed withPd/C (10%, 5 mg) in dichloromethane/methanol (1:1, 2 mL) and stirredunder 1 atmosphere of hydrogen overnight. The reaction mixture wasfiltered through celite, concentrated and chromatographed on a silicacolumn, eluting with CH₂Cl₂/MeOH (85/15) to provide7-(3-aminopropyl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one(45 mg, 89%). MS m/z 349.3 [M+H]⁺.

Step D: Following the procedure in Example 23, the above product fromStep B (45 mg, 0.13 mmol), formaldehyde (0.05 mL, 37%, ˜0.8 mmol) andsodium triacetoxyborohydride (50 mg, 0.24 mmol) indichloromethane/methanol (10:1, 1 mL) provided the title compound as awhite solid (20 mg, 41%). M.P. 136-138° C.; MS m/z 377.3 [M+H]⁺; ¹H NMR(DMSO-d₆, 500 MHz) δ 8.84 (d, J=1.6 Hz, 1H), 8.58 (d, J=1.6 Hz, 1H),8.00 (d, J=9 Hz, 1H), 7.77 (d, J=9 Hz, 1H), 7.60 (d, J=1.6 Hz, 1H), 7.02(s, 1H), 2.79-2.75 (m, 5H), 2.45 (s, 3H), 2.25 (t, J=10 Hz, 2H), 2.15(bs, 6H), 1.83-1.76 (m, 2H).

As shown in Table 1 below, additional compounds disclosed herein may beprepared according to Example 52 by substituting the appropriatestarting materials, reagents and reaction conditions.

Example 53 Preparation of Cpd 407

Step A: A mixture of7-bromo-2-(3,4-dimethoxyphenyl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one(1.5 g, 4.0 mmol, prepared in a manner exemplified in Example 22, StepsA and B), 1,4-dioxa-8-azaspiro[4.5]decane (660 μL, 5.05 mmol), S-Phos(140 mg, 0.34 mmol), Pd₂(dba)₃ (92 mg, 0.1 mmol), Cs₂CO₃ (3.0 g, 9.2mmol), and DME (12 mL) was heated under argon at 90° C. for 3 hours. Thereaction mixture was then suspended in a solution of CH₂Cl₂ and acetone,and was filtered. The filtrate was concentrated under vacuum.Purification by silica gel chromatography (1:1 CH₂Cl₂/EtOAc, then 20%acetone in CH₂Cl₂), followed by trituration with 1:1 hexanes/ether,yielded2-(3,4-dimethoxyphenyl)-9-methyl-7-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-4H-pyrido[1,2-a]pyrimidin-4-one(878 mg, 50%) as a yellow solid. MS m/z 438.2 [M+H]⁺.

Step B: A solution of2-(3,4-dimethoxyphenyl)-9-methyl-7-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-4H-pyrido[1,2-a]pyrimidin-4-one(875 mg, 2.0 mmol) in CH₂Cl₂/dioxane (1:1 v/v, 28 mL) was treated with 6N HCl (7 mL). The mixture was stirred at room temperature for 20minutes, then made basic with aqueous K₂CO₃. The mixture was extractedinto CH₂Cl₂. The organic layer was dried over MgSO₄, filtered, andconcentrated under vacuum. Trituration with 1:1 hexanes/acetone yielded2-(3,4-dimethoxyphenyl)-9-methyl-7-(4-oxopiperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one(758 mg, 96%) as a yellow solid. MS m/z 394.3 [M+H]⁺; ¹H NMR (500 MHz,DMSO-d₆): δ 8.27 (1H, d J=2.5 Hz), 8.08 (1H, s), 7.85 (1H, dd, J=8.5 Hz,2.5 Hz), 7.81 (1H, m), 7.09 (1H, d, J=8.5 Hz), 6.96 (1H, s), 3.88 (3H,s), 3.84 (3H, s), 3.67 (4H, t, J=6 Hz), 2.64 (3H, s), 2.53 (4H, m,obscured by DMSO-d₆).

Step C: A mixture of2-(3,4-dimethoxyphenyl)-9-methyl-7-(4-oxopiperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one(50 mg, 0.13 mmol), NaBH(OAc)₃ (65 mg, 0.31 mmol), DCE (500 L), andn-propylamine (40 μL, 0.49 mmol) was heated at 70° C. for 15 minutes.The reaction mixture was partitioned between aqueous K₂CO₃ and CH₂Cl₂.The organic layer was concentrated under vacuum. Purification by silicagel chromatography (10% MeOH in CH₂Cl₂, followed by 9:1:0.1CH₂Cl₂:MeOH:NH₄OH) yielded the title compound (47 mg, 87%) as a yellowsolid. M.P. 178-184° C.; MS m/z 437.5 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆):δ 8.17 (1H, d, J=3 Hz), 8.00 (1H, m), 7.84 (1H, dd, J=8.5 Hz, 2 Hz),7.80 (1H, d, J=2 Hz), 7.08 (1H, d, J=8.5 Hz), 6.95 (1H, s), 3.88 (3H,s), 3.84 (3H, s), 3.67 (2H, d, J=12.5 Hz), 2.84 (2H, t, J=12.5 Hz), 2.61(3H, s), 2.57 (1H, m), 2.54 (2H, m, obscured by DMSO-d₆ peak), 1.95 (2H,d, J=12.5 Hz), 1.41 (4H, m), 0.89 (3H, t, J=7.5 Hz).

As shown in Table 1 below, additional compounds disclosed herein may beprepared according to Example 53 by substituting the appropriatestarting materials, reagents and reaction conditions.

Example 54 Preparation of Cpd 322

Step A: Into a mixture of 2-methylbenzo[d]oxazole-6-carboxylic acid(2.54 g, 14.4 mmol) and SOCl₂ (2.05 g, 17.2 mmol) in toluene (70 mL) wasadded 6 drops of DMF. The mixture was then stirred at 70° C. for 3hours, cooled and evaporated to give 2-methylbenzo[d]oxazole-6-carbonylchloride as an oil, which solidified on standing (2.9 g, 100%). ¹H NMR(500 MHz, CDCl₃) δ 8.27-8.30 (1H, m), 8.13 (1H, dd, J=8.4, 1.7 Hz), 7.74(1H, dd, J=8.5, 0.6 Hz), 2.73 (3H, s).

Step B: Following the procedure in Example 31, Part 1, Step A, reactionof 2-methylbenzo[d]oxazole-6-carbonyl chloride (2.9 g, 14.4 mmol),dimethylmalonate (1.9 g, 14.4 mmol), MgCl₂ (1.37 g, 14.4 mmol), andtriethylamine (2.9 mL, 28.8 mmol) in acetonitrile (15 mL) provideddimethyl 2-(2-methylbenzo[d]oxazole-6-carbonyl)malonate (2.75 g, 66%).MS m/z 292.0 [M+H]⁺.

Step C: Following the procedure in Example 31, Part 1, Step B, reactionof dimethyl 2-(2-methylbenzo[d]oxazole-6-carbonyl)malonate (2.75 g, 9.5mmol), POCl₃ (10 mL) and DIPEA (2.6 mL, 15.8 mmol) provided dimethyl2-(chloro(2-methylbenzo[d]oxazol-6-yl)methylene)malonate (0.7 g, 24%).MS m/z 310.1 [M+H]⁺.

Step D: Following the procedure in Example 33, Step B and C, reaction ofdimethyl 2-(chloro(2-methylbenzo[d]oxazol-6-yl)methylene)malonate (0.7g, 2.3 mmol), tert-butyl 2-(5-fluoropyridin-2-yl)acetate (0.57 g, 2.7mmol), prepared as in Example 33, Step A, NaH (0.18 g, 4.5 mmol) in DMFfollowed by reaction with TFA and water at 100° C. provided2-(4-amino-3-hydroxyphenyl)-7-fluoro-4H-quinolizin-4-one (0.3 g, 48%).MS m/z 271.2 [M+H]⁺.

Step E: Into a mixture of2-(4-amino-3-hydroxyphenyl)-7-fluoro-4H-quinolizin-4-one (0.3 g, 1.1mmol) and trimethyl orthoformate (1.4 mL, 11.1 mmol) was added TFA (0.13mL, 1.8 mmol). The mixture was stirred for 2 hours at room temperatureand then evaporated to give7-fluoro-2-(2-methylbenzo[d]oxazol-6-yl)-4H-quinolizin-4-one (0.3 g,99%). MS m/z 295.2 [M+H]⁺.

Step F: A mixture of7-fluoro-2-(2-methylbenzo[d]oxazol-6-yl)-4H-quinolizin-4-one (0.15 g,0.51 mmol) and (S)-2-methylpiperazine (0.2 g, 2.0 mmol) in DMA (1.0 mL)was stirred at 130° C. overnight. The solvent was removed by a stream ofnitrogen and the residue was purified with methanol in dichloromethane(10%) to give the title compound as a yellow solid (69 mg, 36%). M.P.115-117° C.; MS m/z 375.3 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃) δ 8.55 (1H, d,J=2.2 Hz), 7.79 (1H, d, J=1.3 Hz), 7.73 (1H, d, J=7.9 Hz), 7.64 (1H, dd,J=8.2, 1.6 Hz), 7.49 (1H, d, J=9.5 Hz), 7.33 (1H, d, J=2.5 Hz),6.86-6.91 (2H, m), 3.60 (2H, br. s.), 3.25-3.34 (1H, m), 3.10-3.22 (2H,m), 2.93-3.03 (1H, m), 2.62-2.70 (4H, m), 1.31 (3H, d, J=6.3 Hz).

As shown in Table 1 below, additional compounds disclosed herein may beprepared according to Example 54 by substituting the appropriatestarting materials, reagents and reaction conditions.

Example 55 Preparation of Cpd 380

Part 1, Step A: A mixture of 6-chloropyridazin-3-amine (0.26 g, 2.0mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(0.62 g, 2.0 mmol), PdCl₂dppf (0.16 g, 0.2 mmol), K₂CO₃ (2.0 M, 3.0 mL,6.0 mmol) in acetonitrile (6.0 mL) was stirred at 100° C. overnight.Aqueous workup followed by purification with methanol in dichloromethane(0-10%) provided tert-butyl4-(6-aminopyridazin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.51 g,93%). MS m/z 277.2 [M+H]⁺.

Part 1, Step B: A solution of tert-butyl4-(6-aminopyridazin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.4 g,1.4 mmol) in ethanol (25 mL) was hydrogenated using Pd(OH)₂ on carbon(20%, 0.2 g) in a Parr shaker (60 psi) overnight. The mixture wasfiltered through Celite, evaporated and purified with methanol indichloromethane (0-10%) to give tert-butyl4-(6-aminopyridazin-3-yl)piperidine-1-carboxylate (0.25 g, 62%). MS m/z279.2 [M+H]⁺.

Part 2, Into a solution of 6-iodo-2-methylbenzo[d]thiazole (2.24 g, 7.3mmol) in THF (15 mL) at −20° C. was added i-PrMgCl in THF (2.0 M, 3.7mL, 7.4 mmol). The mixture was kept between −10° C. to −20° C. for 1hour, then transferred via a cannula to a solution of5-(bis(methylthio)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (1.4 g,5.6 mmol) in THF (15 mL). The reaction was slightly exothermic. Themixture was stirred at room temperature for 90 minutes before quenchingwith aqueous NH₄Cl solution. Aqueous workup followed by purificationwith ethyl acetate in dichloromethane (0-10%) provided2,2-dimethyl-5-((2-methylbenzo[d]thiazol-6-yl)(methylthio)methylene)-1,3-dioxane-4,6-dione(1.26 g, 64%). MS m/z 350.1 [M+H]⁺.

Part 3, A mixture of2,2-dimethyl-5-((2-methylbenzo[d]thiazol-6-yl)(methylthio)methylene)-1,3-dioxane-4,6-dione(0.13 g, 0.36 mmol) and tert-butyl4-(6-aminopyridazin-3-yl)piperidine-1-carboxylate (0.1 g, 0.36 mmol) indiphenyl ether (2.0 mL) was stirred at 140° C. for 1 hour. Thetemperature was then raised to 240° C. and stirred for 30 minutes. Themixture was evaporated and the residue was purified by prep HPLC to givethe title compound as a yellow solid (33 mg, 24%) trifluoroacetic acidsalt. M.P. 230-235° C.; MS m/z 378.2 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ8.87-8.92 (1H, m), 8.28-8.33 (1H, m), 8.08 (1H, d, J=9.1 Hz), 7.99-8.04(1H, m), 7.79 (1H, s), 7.26 (1H, s), 3.41-3.48 (2H, m), 3.22-3.32 (1H,m), 3.03-3.11 (2H, m), 2.84 (3H, s), 2.14-2.22 (2H, m), 2.08 (1H, s),1.92-2.03 (2H, m).

Example 56 Preparation of Cpd 398

Step A: Following the procedure of Example 9, Step G, reaction of6-chloropyridazin-3-amine (0.65 g, 5.0 mmol), ethyl3-(3,4-dimethoxyphenyl)-3-oxopropanoate (1.77 g, 7.0 mmol) and PPTs (63mg, 0.25 mmol) provided7-chloro-2-(3,4-dimethoxyphenyl)-4H-pyrimido[1,2-b]pyridazin-4-one (0.23g, 14%). MS m/z 318.1 [M+H]⁺.

Step B: Following the procedure of Example 34, Step C, reaction of7-chloro-2-(3,4-dimethoxyphenyl)-4H-pyrimido[1,2-b]pyridazin-4-one (0.12g, 0.38 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(0.14 g, 0.45 mmol), PdCl₂dppf (35 mg, 0.038 mmol), K₂CO₃ (2.0 M, 0.6mL, 1.2 mmol) in acetonitrile (1.2 mL) provided tert-butyl4-(2-(3,4-dimethoxyphenyl)-4-oxo-4H-pyrimido[1,2-b]pyridazin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylate(100 mg, 56%). MS m/z 465.3 [M+H]⁺.

Step C: Following the procedure of Example 34, Step D, treatment oftert-butyl4-(2-(3,4-dimethoxyphenyl)-4-oxo-4H-pyrimido[1,2-b]pyridazin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylate (100 mg, 0.21 mmol) with TFA (1.0mL) and dichloromethane (1.0 mL) provided the title compound as a yellowsolid (50 mg, 65%). M.P. 195-200° C.; MS m/z 365.3 [M+H]⁺; ¹H NMR (500MHz, DMSO-d₆) δ 8.13 (1H, d, J=9.8 Hz), 7.96 (1H, d, J=9.8 Hz), 7.82(1H, dd, J=8.5, 2.2 Hz), 7.74 (1H, d, J=2.2 Hz), 7.15 (1H, s), 7.08 (1H,d, J=8.8 Hz), 7.01 (1H, br. s.), 3.87 (3H, s), 3.83 (3H, s), 3.57 (2H,br. s.), 3.00 (2H, br. s.), 2.58 (2H, br. s.).

Example 57 Preparation of Cpd 402

Step A: A mixture of 5-bromopyrazin-2-amine (0.17 g, 1.0 mmol) andbis(2,4,6-trichlorophenyl)malonate (0.56 g, 1.2 mmol) in THF (4.0 mL)was stirred at 88° C. for 1 hour. The mixture was then filtered and thesolid was washed with ethyl acetate. The cake was collected and dried togive 7-bromo-2-hydroxy-4H-pyrazino[1,2-a]pyrimidin-4-one (0.18 g, 74%).MS m/z 242.0 [M+H]⁺, 244.0 [M+2+H]⁺.

Step B: Following the procedure of Example 34, Step C, reaction of7-bromo-2-hydroxy-4H-pyrazino[1,2-a]pyrimidin-4-one (0.18 g, 0.74 mmol),tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(0.27 g, 0.89 mmol), PdCl₂dppf (60 mg, 0.074 mmol), K₂CO₃ (0.31 g, 2.2mmol) in DMF (2.5 mL) provided tert-butyl4-(2-hydroxy-4-oxo-4H-pyrazino[1,2-a]pyrimidin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.18 g, 70%). MS m/z 345.3 [M+H]⁺.

Step C: Into a solution of tert-butyl4-(2-hydroxy-4-oxo-4H-pyrazino[1,2-a]pyrimidin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylate(0.18 g, 0.52 mmol) in DMF (3.0 mL) at room temperature was added NaH(60%, 23 mg, 0.57 mmol). The mixture was stirred for 15 minutes thenPhNTf₂ (0.22 g, 0.62 mmol) was added in one portion. The mixture wasstirred overnight. Aqueous workup followed by purification with ethylacetate in dichloromethane (0-20%) provided tert-butyl4-(4-oxo-2-(trifluoromethylsulfonyloxy)-4H-pyrazino[1,2-a]pyrimidin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylate(0.1 g, 40%). MS m/z 377.1 [M−Boc+H]⁺.

Step D: A mixture of tert-butyl4-(4-oxo-2-(trifluoromethylsulfonyloxy)-4H-pyrazino[1,2-a]pyrimidin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylate(80 mg, 0.17 mmol), 3,4-dimethoxyphenylboronic acid (46 mg, 0.25 mmol),PdCl₂dppf (14 mg, 0.017 mmol), K₃PO₄ (54 mg, 0.25 mmol) in dioxane (2.0mL) was stirred at 100° C. for 24 hours. The mixture was filtered,evaporated and purified with ethyl acetate in dichloromethane (0-20%) togive tert-butyl4-(2-(3,4-dimethoxyphenyl)-4-oxo-4H-pyrazino[1,2-a]pyrimidin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylate(43 mg, 55%). ¹H NMR (500 MHz, CDCl₃) δ 9.10 (1H, s), 8.61 (1H, s), 7.72(1H, s), 7.70 (1H, d, J=1.8 Hz), 7.00 (3H, m), 4.19-4.26 (2H, m), 4.03(3H, s), 3.98 (3H, s), 3.69-3.76 (2H, m), 2.56-2.67 (2H, m), 1.51 (9H,s).

Step E: Following the procedure of Example 34, Step D, treatment oftert-butyl4-(2-(3,4-dimethoxyphenyl)-4-oxo-4H-pyrazino[1,2-a]pyrimidin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylate(43 mg, 0.09 mmol) with TFA (1.0 mL) and dichloromethane (1.0 mL)provided the title compound as a yellow solid (34 mg, 100%). M.P.205-208° C.; MS m/z 365.4 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 9.15 (1H,d, J=0.9 Hz), 8.41 (1H, s), 7.85-7.94 (1H, m), 7.78 (1H, d, J=1.9 Hz),7.27 (1H, s), 7.11 (1H, d, J=8.5 Hz), 6.97-7.05 (1H, m), 3.89 (3H, s),3.84 (3H, s), 3.58 (2H, br. s.), 3.21-3.42 (3H, m), 3.07 (2H, t, J=5.7Hz).

As shown in Table 1 below, additional compounds disclosed herein may beprepared according to Example 57 by substituting the appropriatestarting materials, reagents and reaction conditions.

Example 58 Preparation of Cpd 499

Step A: A mixture of tert-butyl4-(6-aminopyridazin-3-yl)piperidine-1-carboxylate (0.88 g, 3.2 mmol) andbis(2,4,6-trichlorophenyl) malonate (1.76 g, 3.8 mmol) in THF (12 mL)was stirred at 40° C. for 1 hour. The mixture was then evaporated andpurified with methanol in dichloromethane (0-10%) to give tert-butyl4-(2-hydroxy-4-oxo-4H-pyrimido[1,2-b]pyridazin-7-yl)piperidine-1-carboxylate(0.69 g, 63%). MS m/z 347.2 [M+H]⁺.

Step B: Following the procedure of Example 57, Step C, reaction oftert-butyl4-(2-hydroxy-4-oxo-4H-pyrimido[1,2-b]pyridazin-7-yl)piperidine-1-carboxylate(0.69 g, 2.0 mmol), NaH (60%, 88 mg, 2.2 mmol), PhNTf₂ (0.79 g, 2.2mmol) in DMF (12 mL) provided tert-butyl 4-(4-oxo-2-(trifluoromethylsulfonyloxy)-4H-pyrimido[1,2-b]pyridazin-7-yl)piperidine-1-carboxylate(0.87 g, 91%). ¹H NMR (500 MHz, CDCl₃) δ 7.90 (1H, d, J=9.5 Hz), 7.61(1H, d, J=9.5 Hz), 6.45 (1H, s), 4.28-4.36 (2H, m), 3.20-3.30 (1H, m),2.82-2.93 (2H, m), 1.94-2.02 (2H, m), 1.75-1.85 (2H, m), 1.49 (9H, s).

Step C: A mixture of tert-butyl4-(4-oxo-2-(trifluoromethylsulfonyloxy)-4H-pyrimido[1,2-b]pyridazin-7-yl)piperidine-1-carboxylate(0.24 g, 0.5 mmol), 2-methyl-6-(trimethylstannyl)benzo[d]oxazole (0.18g, 0.6 mmol), Pd(PPh₃)₄ (58 mg, 0.05 mmol), CuI (23 mg, 0.12 mmol) indioxane (2.0 mL) was stirred at 90° C. overnight. The mixture wasconcentrated and purified with methanol in dichloromethane (0-10%). Thedesired fractions were combined and evaporated. The residue was treatedwith TFA (1.0 mL) and dichloromethane (1.0 mL) and worked up asdescribed in Example 34, Step D to give the title compound as a yellowsolid (86 mg, 48%). M.P. 126-128° C.; MS m/z 362.2 [M+H]⁺; ¹H NMR (500MHz, methanol-d₄) δ 8.20 (1H, s), 7.91-7.99 (2H, m), 7.67 (2H, d, J=8.2Hz), 7.07 (1H, s), 3.45 (2H, d, J=12.3 Hz), 3.07-3.21 (2H, m), 3.30-3.24(1H, m), 2.61 (3H, s), 2.14 (4H, br. s.).

As shown in Table 1 below, additional compounds disclosed herein may beprepared according to Example 58 by substituting the appropriatestarting materials, reagents and reaction conditions.

Example 59 Preparation of Cpd 502

Step A: A mixture of tert-butyl4-(5-aminopyrazin-2-yl)piperidine-1-carboxylate (0.2 g, 0.72 mmol),ethyl 3-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-3-oxopropanoate (0.21g, 0.79 mmol), Si(OEt)₄ (0.16 mL, 0.72 mmol), PPTs (18 mg, 0.072 mmol)in m-xylene (0.36 mL) was stirred at 60° C. for 1 hour then 130° C.overnight. The mixture was cooled and loaded directly onto a silicacolumn and purified with methanol in dichloromethane (0-10%). Furtherpurification with ethyl acetate in dichloromethane (20-100%) providedtert-butyl4-(2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4-oxo-4H-pyrazino[1,2-a]pyrimidin-7-yl)piperidine-1-carboxylate(0.117 g, 34%). MS m/z 476.4 [M+H]⁺.

Step B: Following the procedure of Example 34, Step D, treatment oftert-butyl4-(2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4-oxo-4H-pyrazino[1,2-a]pyrimidin-7-yl)piperidine-1-carboxylate(117 mg, 0.25 mmol) with TFA (1.0 mL) and dichloromethane (2.0 mL)provided the title compound as a yellow solid (93 mg, 100%). MS m/z376.4 [M+H]⁺; ¹H NMR (500 MHz, methanol-d₄) δ 9.13 (1H, d, J=1.3 Hz),8.53 (1H, s), 8.27 (1H, d, J=0.6 Hz), 7.55 (1H, d, J=1.3 Hz), 7.28 (1H,s), 3.27-3.34 (2H, m), 2.99-3.09 (1H, m), 2.85-2.96 (2H, m), 2.75 (3H,s), 2.47 (3H, d, J=0.9 Hz), 2.05-2.14 (2H, m), 1.84-1.95 (2H, m).

As shown in Table 1 below, additional compounds disclosed herein may beprepared according to Example 59 by substituting the appropriatestarting materials, reagents and reaction conditions.

Example 60 Preparation of Cpd 512

Step A: Following the procedure of Example 59, Step A, the reaction oftert-butyl 4-(6-aminopyridazin-3-yl)piperidine-1-carboxylate (0.28 g,1.0 mmol), ethyl3-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-3-oxopropanoate (0.28 g, 1.1mmol), Si(OEt)₄ (0.22 mL, 1.0 mL), PPTs (25 mg, 0.1 mmol) in m-xylene(0.5 mL) provided tert-butyl4-(2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4-oxo-4H-pyrimido[1,2-b]pyridazin-7-yl)piperidine-1-carboxylate(60 mg, 13%). MS m/z 476.4 [M+H]⁺.

Step B: Following the procedure of Example 34, Step D, treatment oftert-butyl4-(2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4-oxo-4H-pyrimido[1,2-b]pyridazin-7-yl)piperidine-1-carboxylate(60 mg, 0.13 mmol) with TFA (1.0 mL) and dichloromethane (1.0 mL)provided the title compound as a yellow solid (47 mg, 100%). MS m/z376.4 [M+H]⁺; ¹H NMR (500 MHz, methanol-d₄) δ 8.27-8.31 (1H, m), 8.06(1H, d, J=9.5 Hz), 7.78 (1H, s), 7.57 (1H, d, J=0.9 Hz), 7.39 (1H, s),3.25-3.30 (2H, m), 3.15-3.23 (1H, m), 2.82-2.90 (2H, m), 2.79 (3H, s),2.51 (3H, d, J=0.9 Hz), 2.02-2.09 (2H, m), 1.85-1.96 (2H, m).

Example 61 Preparation of Cpd 586

Step A: A mixture of 2,5-dibromopyrazine (1.45 g, 6.1 mmol), tert-butylpiperazine-1-carboxylate (1.13 g, 6.1 mmol) and K₂CO₃ (1.26 g, 9.2 mmol)in NMP (6.0 mL) was stirred at 120° C. overnight. The mixture wascooled, then aqueous workup followed by purification with ethyl acetatein dichloromethane (0-15%) provided tert-butyl4-(5-bromopyrazin-2-yl)piperazine-1-carboxylate (1.45 g, 69%). MS m/z343.3 [M+H]⁺, 345.3 [M+2+H]⁺.

Step B: A mixture of tert-butyl4-(5-bromopyrazin-2-yl)piperazine-1-carboxylate (1.25 g, 3.6 mmol),LiHMDS (1.0 M, 4.4 mL, 4.4 mmol), Pd(dba)₂ (105 mg, 0.18 mmol), P^(t)Bu₃HBF₄ (53 mg, 0.18 mmol) in toluene (4.4 mL) was stirred at 40° C.overnight under an Ar atmosphere. The mixture was then cooled, treatedwith acetonitrile (2.0 mL) and 1N HCl (0.2 mL), stirred for 15 minutesand purified over silica gel with methanol in dichloromethane (0-10%) togive tert-butyl 4-(5-aminopyrazin-2-yl)piperazine-1-carboxylate (0.96 g,94%). MS m/z 280.2 [M+H]⁺.

Step C: A mixture of tert-butyl4-(5-aminopyrazin-2-yl)piperazine-1-carboxylate (0.68 g, 2.4 mmol),bis(2,4,6-trichlorophenyl) malonate (1.36 g, 2.9 mmol) in THF (15 mL)was stirred at room temperature for 64 hours. The mixture was thenfiltered. The solid was washed with ethyl acetate and dried to givetert-butyl4-(2-hydroxy-4-oxo-4H-pyrazino[1,2-a]pyrimidin-7-yl)piperazine-1-carboxylate(0.65 g, 77%). MS m/z 348.3 [M+H]⁺.

Step D: Following the procedure in Example 57, Step C, reaction oftert-butyl4-(2-hydroxy-4-oxo-4H-pyrazino[1,2-a]pyrimidin-7-yl)piperazine-1-carboxylate(0.65 g, 1.9 mmol), NaH (60%, 82 mg, 2.1 mmol) and PhNTf₂ (0.74 g, 2.1mmol) in DMF (10 mL) provided tert-butyl4-(4-oxo-2-(trifluoromethylsulfonyloxy)-4H-pyrazino[1,2-a]pyrimidin-7-yl)piperazine-1-carboxylate(0.72 g, 80%). MS m/z 480.2 [M+H]⁺.

Step E: Following the procedure in Example 57, Step D, reaction oftert-butyl4-(4-oxo-2-(trifluoromethylsulfonyloxy)-4H-pyrazino[1,2-a]pyrimidin-7-yl)piperazine-1-carboxylate(0.38 g, 0.79 mmol) and 2-methyl-2H-indazol-5-ylboronic acid (0.21 g,1.2 mmol) in the presence of PdCl₂dppf (64 mg, 0.08 mmol) an K₃PO₄ (0.25g, 1.2 mmol) in dioxane (6.0 mL) provided tert-butyl4-(2-(2-methyl-2H-indazol-5-yl)-4-oxo-4H-pyrazino[1,2-a]pyrimidin-7-yl)piperazine-1-carboxylate(0.22 g, 60%). MS m/z 462.3 [M+H]⁺.

Step F: Following the procedure of Example 34, Step D, treatment oftert-butyl4-(2-(2-methyl-2H-indazol-5-yl)-4-oxo-4H-pyrazino[1,2-a]pyrimidin-7-yl)piperazine-1-carboxylate(0.22 g, 0.48 mmol) with TFA (1.0 mL) and dichloromethane (1.0 mL)provided the title compound as a yellow solid (0.17 mg, 99%). M.P.160-162° C.; MS m/z 362.3 [M+H]⁺; ¹H NMR (500 MHz, methanol-d₄) δ 9.04(1H, d, J=1.3 Hz), 8.50 (1H, dd, J=1.6, 0.9 Hz), 8.18 (1H, s), 7.97-8.02(2H, m), 7.71 (1H, d, J=9.1 Hz), 7.01 (1H, s), 4.23 (3H, s), 3.61-3.67(4H, m), 3.13-3.20 (4H, m).

Example 62 Preparation of Cpd 695

Part 1, Step A: Into a suspension of 1-(1H-pyrrol-2-yl)ethanone (2.18 g,20 mmol) in dichloromethane (100 mL) at −78° C. was added a solution ofbromine (1.23 mL, 24 mmol) in dichloromethane (25 mL) dropwise over 30minutes. The mixture was stirred for 10 minutes at −78° C. after theaddition and then poured into ice-water. The aqueous layer was extractedwith dichloromethane. The organic extracts were combined, dried andevaporated. The residue was purified with ethyl acetate indichloromethane (0-20%) to give 1-(4-bromo-1H-pyrrol-2-yl)ethanone (3.48g, 92%). MS m/z 188.0 [M+H]⁺, 190.0 [M+2+H]⁺.

Part 1, Step B: Into a solution of 1-(4-bromo-1H-pyrrol-2-yl)ethanone(3.48 g, 18.5 mmol) in DMF (40 mL) at 0° C. was added NaH (60%, 0.81 g,20.4 mmol) portionwise. The temperature was allowed to rise to roomtemperature and 1-chloropropan-2-one (1.54 mL, 19.4 mmol) was addeddropwise. The mixture was stirred at room temperature overnight. Aqueousworkup followed by purification with ethyl acetate in hexane (5-30%)provided 1-(2-acetyl-4-bromo-1H-pyrrol-1-yl)propan-2-one (2.9 g, 64%).¹H NMR (500 MHz, CDCl₃) δ 6.99 (1H, d, J=1.9 Hz), 6.77 (1H, d, J=1.6Hz), 5.00 (2H, s), 2.39 (3H, s), 2.25 (3H, s).

Part 1, Step C: A mixture of1-(2-acetyl-4-bromo-1H-pyrrol-1-yl)propan-2-one (2.9 g, 11.9 mmol) andammonium acetate (18 g, 238 mmol) in acetic acid (100 mL) was stirred at120° C. overnight. The acetic acid was then removed by rotaryevaporation, then ice water was added to the residue and the mixture wasmade basic with NaOH to pH 9. The mixture was extracted with ethylacetate. The organic extracts were combined, dried, and evaporated. Theresidue was purified with ethyl acetate in dichloromethane (0-10%) toprovide 7-bromo-1,3-dimethylpyrrolo[1,2-a]pyrazine (2.4 g, 90%). MS m/z225.1 [M+H]⁺, 227.1 [M+2+H]⁺.

Part 1, Step D: Following the procedure in Example 14, Part 2, reactionof 7-bromo-1,3-dimethylpyrrolo[1,2-a]pyrazine (0.67 g, 3.0 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.99 g, 3.9mmol), PdCl₂dppf (0.24 g, 0.3 mmol), KOAc (0.88 g, 9.0 mmol) in dioxane(10 mL) provided1,3-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-a]pyrazine,which was used directly in the next step without further purification.MS m/z 191.2 [M−pinacol+H]⁺.

Part 2, Step A: Following the procedure in Example 14, Part 3, Step A,reaction of 2-chloro-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one (0.3 g,1.5 mmol) with1,3-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-a]pyrazine(1.5 mmol) provided2-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one(0.34 g, 740). MS m/z 309.2 [M+H]⁺.

Part 2, Step B: Following the procedure in Example 14, Part 3, Step B,reaction of2-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one(0.14 g, 0.45 mmol) with 2,6-dimethylpiperazine (0.26 g, 2.27 mmol)provided the title compound as a yellow solid (57 mg, 320). M.P.254-256° C.; MS m/z 403.4 [M+H]⁺; ¹H NMR (500 MHz, methanol-d₄) δ 8.20(1H, d, J=2.8 Hz), 7.99 (1H, d, J=1.6 Hz), 7.84-7.90 (1H, m), 7.72 (1H,d, J=0.6 Hz), 7.58 (1H, d, J=9.5 Hz), 7.25 (1H, t, J=1.1 Hz), 6.69 (1H,s), 3.60 (2H, d, J=9.5 Hz), 3.03-3.11 (2H, m), 2.62 (3H, s), 2.37 (2H,t, J=11.3 Hz), 2.31 (3H, d, J=0.9 Hz), 1.21 (6H, d, J=6.3 Hz).

As shown in Table 1 below, additional compounds disclosed herein may beprepared according to Example 62 by substituting the appropriatestarting materials, reagents and reaction conditions.

Example 63 Preparation of Cpd 731

Part 1, Step A: Following the procedure in Example 57, Step A, reactionof 5-chloropyridin-2-amine (2.57 g, 20 mmol) andbis(2,4,6-trichlorophenyl) malonate (10.2 g, 22 mmol) in THF (100 mL)provided 7-chloro-2-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one (3.89 g,97%). ¹H NMR (500 MHz, DMSO-d₆) δ 12.01 (1H, br. s.), 8.89 (1H, d, J=2.2Hz), 8.10 (1H, dd, J=9.3, 2.4 Hz), 7.44 (1H, d, J=9.5 Hz), 5.19 (1H, br.s.).

Part 1, Step B: Following the procedure in Example 57, Step C, reactionof 7-chloro-2-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one (3.89 g, 19.8mmol) with NaH (60%, 0.87 g, 21.8 mmol) and PhNTf₂ (7.78 g, 21.8 mmol)in DMF (50 mL) provided 7-chloro-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yltrifluoromethanesulfonate (5.9 g, 91%). MS m/z 370.0 [M+H]⁺.

Part 2, Step A: Into a solution of7-bromo-1,3-dimethylpyrrolo[1,2-a]pyrazine (1.1 g, 4.9 mmol) in THF (20mL) at −78° C. was added BuLi (1.6 M, 4.7 mL, 7.5 mmol) dropwise. Themixture was stirred at −78° C. for 30 minutes, triisopropyl borate (1.7mL, 7.4 mmol) was added. The temperature was allowed to rise to roomtemperature slowly. The reaction was quenched with water (1.0 mL) andthe mixture was evaporated to dryness under vacuum. Into the residue wasadded 7-chloro-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yltrifluoromethanesulfonate (1.6 g, 4.9 mmol), PdCl₂dppf (0.4 g, 0.49mmol), K₃PO₄ (1.55 g, 7.3 mmol) and dioxane (40 mL). The mixture wasstirred at 100° C. overnight under an Ar atmosphere, after which themixture was cooled, evaporated and purified through silica with methanolin dichloromethane (0-10%) to give7-chloro-2-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-4H-pyrido[1,2-a]pyrimidin-4-one(0.34 g, 22%). MS m/z 325.2 [M+H]⁺.

Part 2, Step B: A mixture of7-chloro-2-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-4H-pyrido[1,2-a]pyrimidin-4-one(0.2 g, 0.62 mmol), tert-butyl 4-methylpiperidin-4-ylcarbamate (0.17 g,0.8 mmol), RuPhos-Pd (22 mg, 0.031 mmol), RuPhos (14 mg, 0.031 mmol) andsodium t-butoxide (83 mg, 0.87 mmol) in THF (1.5 mL) was stirred at 85°C. overnight under an Ar atmosphere. The mixture was then cooled, intowhich was added acetic acid (1.4 eq) and then purified over silica withmethanol in dichloromethane (0-10%) to give tert-butyl1-(2-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)-4-methylpiperidin-4-ylcarbamate(70 mg, 22%). MS m/z 503.4 [M+H]⁺.

Part 2, Step C: The compound tert-butyl1-(2-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)-4-methylpiperidin-4-ylcarbamate(70 mg, 0.14 mmol) was treated with HCl in dioxane (4 N, 1.0 mL) for 30minutes. The solvent was then removed. The residue was re-treated withammonia in methanol and evaporated. The residue was purified withmethanol in dichloromethane (0-10%) to give the title compound as ayellow solid (36 mg, 64%). M.P. 244-246° C.; MS m/z 403.3 [M+H]⁺; ¹H NMR(500 MHz, DMSO-d₆) δ 8.22-8.27 (2H, m), 8.04 (1H, dd, J=9.8, 2.8 Hz),7.96 (1H, s), 7.60 (1H, d, J=9.8 Hz), 7.41 (1H, t, J=1.3 Hz), 6.82 (1H,s), 3.25-3.30 (4H, m), 2.58 (3H, s), 2.27 (3H, d, J=0.9 Hz), 1.47-1.65(6H, m), 1.10 (3H, s).

Example 64 Preparation of Cpd 743

Step A: A mixture of7-chloro-2-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-4H-pyrido[1,2-a]pyrimidin-4-one(0.14 g, 0.43 mmol) and tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(0.2 g, 0.65 mmol), Pd(OAc)₂ (1.9 mg, 0.0086 mmol), SPhos (7.0 mg,0.0172 mmol) and K₃PO₄ (0.18 g, 0.86 mmol) in THF (1.0 mL) and water(0.5 mL) was stirred at 110° C. overnight. Aqueous workup followed bypurification with methanol in dichloromethane (0-10%) providedtert-butyl4-(2-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylate(0.13 g, 65%). MS m/z 472.3 [M+H]⁺.

Step B: Following the procedure in Example 63, Part 2, Step C, treatmentof tert-butyl4-(2-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylate(0.13 g, 0.28 mmol) with HCl in dioxane (1.0 mL) provided the titlecompound as a yellow solid (5 mg, 5%). M.P. 189-191° C.; MS m/z 372.3[M+H]⁺; ¹H NMR (500 MHz, methanol-d₄) δ 8.81 (1H, d, J=1.9 Hz), 8.03(2H, d, J=1.6 Hz), 7.71 (1H, s), 7.62 (1H, d, J=9.5 Hz), 7.28 (1H, s),6.76 (1H, s), 6.41-6.50 (1H, m), 3.58 (2H, d, J=2.5 Hz), 3.15 (2H, t,J=5.8 Hz), 2.63 (3H, s), 2.54 (2H, br. s.), 2.32 (3H, d, J=0.6 Hz).

Example 65 Preparation of Cpd 804

Step A: 5-fluoro-2-nitropyridine (200 mg, 1.41 mmol), tert-butyl2,7-diazaspiro[3.5]-nonane-2-carboxylate (319 mg, 1.41 mmol) and K₂CO₃(195 mg, 1.41 mmol) were combined in DMSO (8 mL). The reaction mixturewas heated at 70° C. for 15 hours and cooled to room temperature, beforethe solvent was evaporated. An extraction (CH₂Cl₂ and H₂O) followed bychromatography with silica gel (CH₂Cl₂/MeOH: 98/2) gave7-(6-nitro-pyridin-3-yl)-2,7-diaza-spiro[3.5]nonane-2-carboxylic acidtert-butyl ester (320 mg, 65%) as a yellow solid. MS m/z 349.5 [M+H]⁺.

Step B: 7-(6-nitro-pyridin-3-yl)-2,7-diaza-spiro[3.5]nonane-2-carboxylicacid tert-butyl ester (315 mg, 0.90 mmol) and Pd/C (32 mg) were combinedin MeOH (40 mL) and placed under a hydrogen atmosphere (H2 balloon) for15 hours. The reaction mixture was filtered through celite andchromatographed with silica gel (CH₂Cl₂/MeOH: 98/2) to give7-(6-amino-pyridin-3-yl)-2,7-diaza-spiro [3.5]nonane-2-carboxylic acidtert-butyl ester (227 mg, 78%) as an off-white solid. MS m/z 319.6[M+H]⁺.

Step C: A mixture of7-(6-amino-pyridin-3-yl)-2,7-diaza-spiro[3.5]nonane-2-carboxylic acidtert-butyl ester (100 mg, 0.31 mmol), ethyl3-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-3-oxopropanoate (90 mg, 0.31mmol, preparation described in Example 9, Steps A to F) and PPTs (87 mg,0.345 mmol) in methyl-1-butanol (2 mL) was heated at 160° C. for 15hours. The mixture was cooled to room temperature, poured into anaqueous NaOH (1M) solution and extracted with CH₂Cl₂. The combinedorganic phases were dried over Na₂SO₄ and the residue waschromatographed with silica gel (CH₂Cl₂/MeOH: 9/1; and, 1% aqueous NH₃)to give the title product (40 mg, 31%) as a yellow solid. MS m/z 416.2[M+H]⁺. ¹H NMR (CDCl₃, 600 MHz) δ 8.18 (d, J=1.1 Hz, 1H), 8.15 (s, 1H),7.45 (dd, 1H) 7.80 (d, 1H), 7.32 (s, 1H), 7.11 (s, 1H), 3.51 (m, 2H),3.42 (d, 1H), 3.36 (d, 1H), 3.15 (m, 2H), 3.00 (d, 1H), 2.97 (d, 1H),2.79 (s, 3H), 2.52 (s, 3H), 2.10 (m, 2H), 1.89 (m, 2H).

Example 66 Preparation of Cpd 811

Step A: 5-Bromopyridin-2-amine (1.0 g, 5.8 mmol) in THE (20 mL), cooledto −78° C. under Ar, was combined with n-BuLi (3.6 ml, 5.8 mmol, 1.6 Min hexanes) and stirred for 0.5 hours.1,2-Bis(chlorodimethylsilyl)ethane (1.2 g, 5.8 mmol) in THF (10 mL) wasadded and the mixture was allowed to warm to ambient temperature over 1hour. The mixture was then re-cooled to −78° C. and a second equivalentof n-BuLi (3.6 ml, 5.8 mmol, 1.6 M in hexanes) was added. The mixturewas stirred for 0.5 hours at −78° C. and then allowed to warm to ambienttemperature over 1 hour. The mixture was then re-cooled to −78° C. and athird equivalent of n-BuLi (3.6 ml, 5.8 mmol, 1.6 M in hexanes) wasadded. The mixture was stirred for 1 hour at −78° C., then tert-butyl4-oxopiperidine-1-carboxylate (1.3 g, 6.4 mmol) in THF (10 mL) was addedand the reaction was allowed to come to ambient temperature. The mixturewas diluted with EtOAc, washed with brine, dried (Na₂SO₄) andconcentrated. The residue was eluted from silica with EtOAc (0-100%) inn-heptane to afford tert-butyl4-(6-aminopyridin-3-yl)-4-hydroxypiperidine-1-carboxylate as a lightyellow solid (1.1 g, 64%). MS m/z 294.2 [M+H]⁺.

Step B: A mixture of bis(2,4,6-trichlorophenyl) malonate (0.80 g, 1.7mmol) and tert-butyl4-(6-aminopyridin-3-yl)-4-hydroxypiperidine-1-carboxylate (0.50 g, 1.7mmol) was heated in toluene (10 mL) at 60° C. for 2 hours. The reactionwas concentrated to remove the volatiles. The residue was eluted fromsilica with MeOH (0-20%) in CH₂Cl₂ to afford tert-butyl4-hydroxy-4-(2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)piperidine-1-carboxylateas a light yellow solid (0.43 g, 70%). MS m/z 362.3 [M+H]⁺.

Step C: A mixture of tert-butyl4-hydroxy-4-(2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)piperidine-1-carboxylate(0.17 g, 0.5 mmol),1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide(0.19 g, 0.5 mmol) and potassium carbonate (0.13 g, 0.9 mmol) in DMF (3mL) was stirred at ambient temperature. After 1 hour, the mixture wasdiluted with EtOAc, washed with water, brine, dried (Na₂SO₄) andconcentrated. The residue was eluted from silica with EtOAc (10-50%) inn-heptane to afford tert-butyl4-hydroxy-4-(4-oxo-2-(trifluoromethylsulfonyloxy)-4H-pyrido[1,2-a]pyrimidin-7-yl)piperidine-1-carboxylateas a crystalline yellow solid (0.08 g, 35%). MS m/z 494.3 [M+H]⁺.

Step D: Following the procedure in Example 15, Step A, tert-butyl4-hydroxy-4-(4-oxo-2-(trifluoromethylsulfonyloxy)-4H-pyrido[1,2-a]pyrimidin-7-yl)piperidine-1-carboxylate(80 mg, 0.16 mmol),8-fluoro-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine(67 mg, 0.24 mmol, Prepared in Example 16, Step B),tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.01 mmol) and K₂CO₃ (31mg, 0.32 mmol) in MeCN/water (2 ml/0.3 mL) provided tert-butyl4-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)-4-hydroxypiperidine-1-carboxylateas an off-white crystalline solid (60 mg, 75%). MS m/z 494.5 [M+H]⁺.

Step E: Following the procedure in Example 24, Step B, the above productfrom Step D and HCl in dioxane (4M, 2 mL) provided2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(4-hydroxypiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-oneas a white solid (11 mg, 49%). MS m/z 394.4 [M+H]⁺. ¹H NMR (DMSO-d₆, 300MHz) δ 9.31 (d, J=1.2 Hz, 1H), 9.01 (d, J=1.8 Hz, 1H), 8.12 (dd, J=9.3,1.8 Hz, 1H), 7.96 (d, J=2.4 Hz, 1H), 7.88 (dd, J=12.6, 1.2 Hz, 1H), 7.75(d, J=9.3 Hz, 1H), 7.06 (s, 1H), 5.34 (br s, 1H), 2.91 (apparent t,J=12.0 Hz, 2H), 2.79 (d, J=12.0 Hz, 2H), 2.39 (s, 3H), 1.89-1.84 (m,2H), 1.60 (d, J=12.0 Hz, 2H).

Table 1 provides isolated compounds of a free base form of a compound ofFormula (I) that may be prepared according to the procedures of theindicated Example by substituting the appropriate starting materials,reagents and reaction conditions. The preparation of any salt,isotopologue, stereoisomer, racemate, enantiomer, diastereomer ortautomer from a free base form of a compound of Formula (I) is alsocontemplated and further included within the scope of the descriptionherein. Where a free base form of the compound was not isolated from thesalt form, a person of ordinary skill in the art could be expected toperform the required reactions to prepare and isolate the free base formof the compound.

The term “Cpd” represents Compound number, the term “Ex” represents“Example Number” (wherein * indicates that the corresponding Example forthe Compound is provided above), the term “M.P.” represents “MeltingPoint (oC),” the term “MS” represents “Mass Spectroscopy Peak(s) m/z[M+H]⁺, [M+2+H]⁺, [M−H]⁻ or [M+2−H]⁻,” the term “D” represents“Decomposition/Decomposed,” the term “DR” represents “DecompositionRange,” the term “S” represents “Softens,” the term “ND” indicates thatthe value was “Not Determined” and the term “NI” indicates that thecompound was “Not Isolated.”

TABLE 1 Ex Cpd Name M.P. MS  4*  12-(4-methoxyphenyl)-7-(piperazin-1-yl)-4H- 182-184 337.3pyrido[1,2-a]pyrimidin-4-one  4  22-(4-methoxyphenyl)-7-(4-methylpiperazin-1-yl)- 178-182 351.34H-pyrido[1,2-a]pyrimidin-4-one  4  32-(4-methoxyphenyl)-7-[(3R)-3-methylpiperazin-1- 152-154 351.3yl]-4H-pyrido[1,2-a]pyrimidin-4-one  4  47-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(4- 185-187 365.3methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one  4  57-(1,4-diazepan-1-yl)-2-(4-methoxyphenyl)-4H- 149-152 351.3pyrido[1,2-a]pyrimidin-4-one  3*  62-(3,4-dimethoxyphenyl)-7-(piperazin-1-yl)-4H- 182-184 367.5pyrido[1,2-a]pyrimidin-4-one  3  72-(3,4-dimethoxyphenyl)-7-(3,3-dimethylpiperazin- 138-140 395.31-yl)-4H-pyrido[1,2-a]pyrimidin-4-one  3  82-(3,4-dimethoxyphenyl)-7-[(3R)-3-methylpiperazin- 181-184 381.31-yl]-4H-pyrido[1,2-a]pyrimidin-4-one  3  92-(3,4-dimethoxyphenyl)-7-(4-ethylpiperazin-1-yl)- 159-162 395.34H-pyrido[1,2-a]pyrimidin-4-one  3  107-(1,4-diazepan-1-yl)-2-(3,4-dimethoxyphenyl)-4H- ND 381.3pyrido[1,2-a]pyrimidin-4-one  3  112-(3,4-dimethoxyphenyl)-7-(4-methyl-1,4-diazepan- 166-168 395.31-yl)-4H-pyrido[1,2-a]pyrimidin-4-one  3  122-(4-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1- 158-160 351.3yl]-4H-pyrido[1,2-a]pyrimidin-4-one  3  132-(3,4-dimethoxyphenyl)-7-(4-methylpiperazin-1- 183-185 381.3yl)-4H-pyrido[1,2-a]pyrimidin-4-one  3  142-(3,4-dimethoxyphenyl)-7-[(3R,5S)-3,5- 182-187 395.3dimethylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin- 4-one  3  152-(3,4-dimethoxyphenyl)-7-(4-propylpiperazin-1-yl)- 185-189 409.34H-pyrido[1,2-a]pyrimidin-4-one  4  162-(4-methoxyphenyl)-7-(4-methyl-1,4-diazepan-1- 137-141 365.3yl)-4H-pyrido[1,2-a]pyrimidin-4-one  4  177-(3,3-dimethylpiperazin-1-yl)-2-(4- ND 365.3methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one  4  182-(1,3-benzodioxol-5-yl)-7-(piperazin-1-yl)-4H- 198-201 351.3pyrido[1,2-a]pyrimidin-4-one  4  192-(1,3-benzodioxol-5-yl)-7-(4-methylpiperazin-1-yl)- 235-237 365.24H-pyrido[1,2-a]pyrimidin-4-one  4  202-(1,3-benzodioxol-5-yl)-7-[(3R)-3-methylpiperazin- 195-197 365.31-yl]-4H-pyrido[1,2-a]pyrimidin-4-one  4  212-(1,3-benzodioxol-5-yl)-7-[(3R,5S)-3,5- 198-201 379.3dimethylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin- 4-one  4  222-(3-methoxyphenyl)-7-(piperazin-1-yl)-4H- 147-149 337.2pyrido[1,2-a]pyrimidin-4-one  4  232-(3-methoxyphenyl)-7-(4-methylpiperazin-1-yl)- 173-175 351.24H-pyrido[1,2-a]pyrimidin-4-one  4  242-(3-methoxyphenyl)-7-[(3R)-3-methylpiperazin-1- 164-166 351.2yl]-4H-pyrido[1,2-a]pyrimidin-4-one  4  257-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(3- 189-191 365.3methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one  4  267-(4-ethylpiperazin-1-yl)-2-(3-methoxyphenyl)-4H- 158-160 365.3pyrido[1,2-a]pyrimidin-4-one  4  277-(1,4-diazepan-1-yl)-2-(3-methoxyphenyl)-4H- ND 351.2pyrido[1,2-a]pyrimidin-4-one  4  282-(3-methoxyphenyl)-7-(4-methyl-1,4-diazepan-1- 130-132 365.2yl)-4H-pyrido[1,2-a]pyrimidin-4-one  8*  292-(6-methylimidazo[1,2-a]pyridin-2-yl)-7-(piperazin- 193-198 361.31-yl)-4H-pyrido[1,2-a]pyrimidin-4-one  3  302-(3,4-dimethoxyphenyl)-7-[(3S)-3-methylpiperazin- 153-158 381.31-yl]-4H-pyrido[1,2-a]pyrimidin-4-one  4  312-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-(piperazin-1- 230-232 365.3yl)-4H-pyrido[1,2-a]pyrimidin-4-one  4  322-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-[(3S)-3- 205-207 379.3methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4- one  3  332-phenyl-7-(piperazin-1-yl)-4H-pyrido[1,2- 151-153 307.2a]pyrimidin-4-one  3  34 7-[(3S)-3-methylpiperazin-1-yl]-2-phenyl-4H-170-173 321.3 pyrido[1,2-a]pyrimidin-4-one  4  352-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-[(3R)-3- 212-214 379.2methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4- one  4  362-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-(3,3- 196-198 393.3dimethylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin- 4-one  4  372-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-[(3R,5S)- 247-250 393.33,5-dimethylpiperazin-1-yl]-4H-pyrido[1,2- a]pyrimidin-4-one  4  387-(1,4-diazepan-1-yl)-2-(2,3-dihydro-1,4- 180-182 379.3benzodioxin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one  4  392-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-(4-methyl- 150-152 393.31,4-diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one  1  402-(3,4-dimethoxyphenyl)-9-fluoro-7-(4- 183-185 399.3methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4- one  1  412-(3-chlorophenyl)-7-(piperazin-1-yl)-4H- 185-189 341.2pyrido[1,2-a]pyrimidin-4-one  1  422-(4-chlorophenyl)-7-(piperazin-1-yl)-4H- 207-212 341.2pyrido[1,2-a]pyrimidin-4-one  1  437-(piperazin-1-yl)-2-[3-(trifluoromethyl)phenyl]-4H- 199-207 375.2pyrido[1,2-a]pyrimidin-4-one  1  447-(piperazin-1-yl)-2-[4-(trifluoromethyl)phenyl]-4H- 285 (D) 375.2pyrido[1,2-a]pyrimidin-4-one  1  452-(3-methylphenyl)-7-(piperazin-1-yl)-4H- 183-187 321.2pyrido[1,2-a]pyrimidin-4-one  1  462-(4-fluorophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2- 214-218 325.2a]pyrimidin-4-one  1  472-(4-nitrophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2- 237-242 352.2a]pyrimidin-4-one  1  482-(3,4-dimethoxyphenyl)-9-fluoro-7-(piperidin-4- 224-226 399.3ylamino)-4H-pyrido[1,2-a]pyrimidin-4-one  3  492-[4-(dimethylamino)phenyl]-9-fluoro-7-(piperazin- 216-218 368.31-yl)-4H-pyrido[1,2-a]pyrimidin-4-one  3  502-[4-(dimethylamino)phenyl]-9-fluoro-7-[(3R)-3- 205-207 382.3methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4- one  1  512-(2-fluorophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2- 142-146 325.2a]pyrimidin-4-one 28*  52 3-(3,4-dimethoxyphenyl)-8-(piperazin-1-yl)-4H-175-179 367.2 pyrido[1,2-a]pyrimidin-4-one  3  532-[4-(dimethylamino)phenyl]-7-(piperazin-1-yl)-4H- 211-215 350.3pyrido[1,2-a]pyrimidin-4-one  3  542-[4-(dimethylamino)phenyl]-7-[(3S)-3- 199-202 364.3methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4- one  3  552-(3,4-dimethylphenyl)-7-(piperazin-1-yl)-4H- 186-188 335.2pyrido[1,2-a]pyrimidin-4-one  3  562-(3,4-dimethylphenyl)-7-[(3S)-3-methylpiperazin-1- 207-209 349.3yl]-4H-pyrido[1,2-a]pyrimidin-4-one  3  572-[3-(dimethylamino)phenyl]-7-(piperazin-1-yl)-4H- 178-180 350.2pyrido[1,2-a]pyrimidin-4-one  3  582-[3-(dimethylamino)phenyl]-7-[(3S)-3- 144-146 364.3methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4- one  3  592-[4-(difluoromethoxy)phenyl]-7-(piperazin-1-yl)- 131-133 373.54H-pyrido[1,2-a]pyrimidin-4-one  3  602-[4-(difluoromethoxy)phenyl]-7-[(3S)-3- 166-168 387.2methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4- one  1  612-(3-fluorophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2- 153-156 325.2a]pyrimidin-4-one  1  622-(3-nitrophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2- 175 (D) 352.2a]pyrimidin-4-one  1  63 2-(4-methylphenyl)-7-(piperazin-1-yl)-4H-192-195 321.2 pyrido[1,2-a]pyrimidin-4-one  3  642-(2-fluoro-4,5-dimethoxyphenyl)-7-(piperazin-1- 177-180 385.2yl)-4H-pyrido[1,2-a]pyrimidin-4-one  3  652-(2-fluoro-4,5-dimethoxyphenyl)-7-[(3S)-3- 167-170 399.2methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4- one  3  667-(3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(3,4- 158-161 393.3dimethoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one  1  672-[4-methoxy-3-(trifluoromethyl)phenyl]-7- 177-181 405.1(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one  1  682-[4-methoxy-3-(trifluoromethyl)phenyl]-7-[(3R)-3- 205-212 419.3methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4- one  1  692-[4-methoxy-3-(trifluoromethyl)phenyl]-7-[(3S)-3- 195-200 419.3methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4- one  6*  702-(3,4-dimethoxyphenyl)-9-methoxy-7-(piperazin-1- 185-187 397.3yl)-4H-pyrido[1,2-a]pyrimidin-4-one 11  71a2-(3,5-difluoro-4-hydroxyphenyl)-7-(piperazin-1-yl)- NI NI4H-pyrido[1,2-a]pyrimidin-4-one  1*  722-(3-fluoro-4-methoxyphenyl)-7-(piperazin-1-yl)- 191-195 355.04H-pyrido[1,2-a]pyrimidin-4-one  3  734-[4-oxo-7-(piperazin-1-yl)-4H-pyrido[1,2- 146-151 332.1a]pyrimidin-2-yl]benzonitrile  7*  742-(6-methylimidazo[1,2-a]pyrazin-2-yl)-7- 221-225 362.2(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one  7  752-(6-methylimidazo[1,2-a]pyrazin-2-yl)-7-[(3S)-3- 235-238 376.2methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4- one  1  762-[3-fluoro-5-(trifluoromethyl)phenyl]-7-(piperazin- ND 3931-yl)-4H-pyrido[1,2-a]pyrimidin-4-one  1  772-[4-fluoro-3-(trifluoromethyl)phenyl]-7-(piperazin- 214-217 393.11-yl)-4H-pyrido[1,2-a]pyrimidin-4-one  1  782-[2-methoxy-3-(trifluoromethyl)phenyl]-7- 194-200 405.1(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one  1  792-(3,5-difluorophenyl)-7-(piperazin-1-yl)-4H- 195-198 343pyrido[1,2-a]pyrimidin-4-one  1  807-(piperazin-1-yl)-2-[3-(trifluoromethoxy)phenyl]- 140-143 3914H-pyrido[1,2-a]pyrimidin-4-one  5*  812-[4-methoxy-3-(trifluoromethoxy)phenyl]-7- 158-162 421.1(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one  5*  822-[4-hydroxy-3-(trifluoromethoxy)phenyl]-7- 245-248 407.2(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one  5  832-[4-methoxy-3-(trifluoromethoxy)phenyl]-7-[(3S)- 176-178 435.93-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin- 4-one  5  842-[4-hydroxy-3-(trifluoromethoxy)phenyl]-7-[(3S)- 152-155 421.23-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin- 4-one 31*  852-(3,4-dimethoxyphenyl)-4-oxo-7-(piperazin-1-yl)- 199-202 391.24H-quinolizine-1-carbonitrile  1  862-(3-fluoro-4-methoxyphenyl)-7-[(3R)-3- 175-178 369.1methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4- one  1  872-(3-fluoro-4-methoxyphenyl)-7-[(3S)-3- 175-178 369.1methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4- one  1  882-(6-methoxypyridin-3-yl)-7-(piperazin-1-yl)-4H- 173-178 338.2pyrido[1,2-a]pyrimidin-4-one  1  892-(2,4-dimethoxyphenyl)-7-(piperazin-1-yl)-4H- 171-173 367.3pyrido[1,2-a]pyrimidin-4-one  1  902-(2,4-dimethoxyphenyl)-7-[(3S)-3-methylpiperazin- 172-177 381.21-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 32*  912-(3,4-dimethoxyphenyl)-7-[(3S)-3-methylpiperazin- 243-245 380.21-yl]-4H-quinolizin-4-one 11*  922-(5-fluoropyridin-3-yl)-7-(piperazin-1-yl)-4H- 201-208 326.2pyrido[1,2-a]pyrimidin-4-one 11  932-(5-fluoropyridin-3-yl)-7-[(3S)-3-methylpiperazin- 191-199 340.11-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 11  942-(5-chloropyridin-3-yl)-7-(piperazin-1-yl)-4H- 208-218 342pyrido[1,2-a]pyrimidin-4-one 11  952-(5-chloropyridin-3-yl)-7-[(3S)-3-methylpiperazin- 227-232 3561-yl]-4H-pyrido[1,2-a]pyrimidin-4-one  1  962-(5-chloro-6-methoxypyridin-3-yl)-7-(piperazin-1- 201-209 372.1yl)-4H-pyrido[1,2-a]pyrimidin-4-one 12  972-(1H-indol-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2- 202-206 346.2a]pyrimidin-4-one 12*  982-(1H-indol-5-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2- 266-272 346.2a]pyrimidin-4-one  3  99 2-[3-(difluoromethoxy)-4-methoxyphenyl]-7- ND403.4 (piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one  3 1002-[3-(difluoromethoxy)-4-hydroxyphenyl]-7- 233-237 389.2(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one  3 1012-[3-(difluoromethoxy)-4-methoxyphenyl]-7-[(3S)- 167-169 4173-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin- 4-one  3 1022-[3-(difluoromethoxy)-4-hydroxyphenyl]-7-[(3S)-3- 192-197 403.2methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4- one 33 1032-(3-fluoro-4-methoxyphenyl)-7-(piperazin-1-yl)- 200-202 354.14H-quinolizin-4-one 33 104 2-(3-fluoro-4-methoxyphenyl)-7-[(3S)-3-188-192 368.1 methylpiperazin-1-yl]-4H-quinolizin-4-one  1 1052-(3,5-difluorophenyl)-7-[(3S)-3-methylpiperazin-1- 189-194 357.2yl]-4H-pyrido[1,2-a]pyrimidin-4-one 33* 1062-(3,4-dimethoxyphenyl)-7-(piperazin-1-yl)-4H- 170-172 366.1quinolizin-4-one 13* 1072-(imidazo[1,2-a]pyridin-7-yl)-7-(piperazin-1-yl)- 258-270 3474H-pyrido[1,2-a]pyrimidin-4-one 12 1082-(imidazo[1,2-a]pyridin-6-yl)-7-(piperazin-1-yl)- ND 3474H-pyrido[1,2-a]pyrimidin-4-one 15* 1092-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperazin- 259-267 361.11-yl)-4H-pyrido[1,2-a]pyrimidin-4-one  3 1102-(3-chloro-4-methoxyphenyl)-7-(piperazin-1-yl)- 201-203 371.4,4H-pyrido[1,2-a]pyrimidin-4-one 373.4  3 1112-(3-chloro-4-methoxyphenyl)-7-[(3S)-3- 187-189 385.5,methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4- 387.5 one  1 1122-(3-ethoxy-4-methoxyphenyl)-7-(piperazin-1-yl)- 194-196 381.14H-pyrido[1,2-a]pyrimidin-4-one  1 1132-(3-ethoxy-4-methoxyphenyl)-7-[(3S)-3- 159-162 395.1methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4- one 15 1142-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(4- ND 375.1methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4- one 15 1152-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-3- ND 375.1methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4- one 15 1167-(1,4-diazepan-1-yl)-2-(2-methylimidazo[1,2- ND 375.1a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 15 1177-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(2- 181-186 389.1methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2- a]pyrimidin-4-one  7118 2-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7- 189-192 376.5(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one  7 1192-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3S)- 202-208 390.53-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin- 4-one  9 1202-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7- 195-200 376.5(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one  9 1212-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3S)- 192-194 390.53-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin- 4-one 22 1222-(3,4-dimethoxyphenyl)-7-(2-methylpyridin-4-yl)- 197-200 3744H-pyrido[1,2-a]pyrimidin-4-one 15 1237-(piperazin-1-yl)-2-[2-(trifluoromethyl)imidazo[1,2- 250-255 415.5a]pyridin-6-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 15 1242-(2-ethylimidazo[1,2-a]pyridin-6-yl)-7-(piperazin- 228-232 375.51-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 15 1252-(2,3-dimethylimidazo[1,2-a]pyridin-6-yl)-7- 236-240 375.5(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one  2 1262-(3,4-dimethoxyphenyl)-7-[(3aR,6aS)- 286-290 393.1hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4H- pyrido[1,2-a]pyrimidin-4-one 2 127 7-(4-aminopiperidin-1-yl)-2-(3,4-dimethoxyphenyl)- 182-185 381.14H-pyrido[1,2-a]pyrimidin-4-one 19* 1287-(piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)- 252-255 347.14H-pyrido[1,2-a]pyrimidin-4-one 19 1292-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-7- 230-233 361.1(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 19 1307-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(1-methyl- 265-268 389.11H-pyrrolo[2,3-b]pyridin-5-yl)-4H-pyrido[1,2- a]pyrimidin-4-one  9 1317-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(4,6- ND 404.5dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H- pyrido[1,2-a]pyrimidin-4-one  9132 7-(1,4-diazepan-1-yl)-2-(4,6-dimethylpyrazolo[1,5- ND 390.5a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 14 1332-(2-methyl-1,3-benzoxazol-6-yl)-7-(piperazin-1-yl)- 219-222 362.54H-pyrido[1,2-a]pyrimidin-4-one 14 1342-(2-methyl-1,3-benzoxazol-6-yl)-7-[(3S)-3- 191-193 376.5methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4- one 14 1352-(2-methyl-1,3-benzothiazol-5-yl)-7-[(3S)-3- 174-180 392.2methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4- one 14 1362-(2-methyl-1,3-benzothiazol-5-yl)-7-(piperazin-1- 228-230 378.1yl)-4H-pyrido[1,2-a]pyrimidin-4-one 14 1372-(2-methyl-2H-indazol-5-yl)-7-(piperazin-1-yl)-4H- 175-180 361.5pyrido[1,2-a]pyrimidin-4-one 14 1382-(2-methyl-2H-indazol-5-yl)-7-[(3S)-3- 166-170 375.5methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4- one 14 1392-(3-fluoro-5-methoxyphenyl)-7-(piperazin-1-yl)- 168-170 355.54H-pyrido[1,2-a]pyrimidin-4-one 14 1402-(3-fluoro-5-methoxyphenyl)-7-[(3S)-3- 154-156 369.5methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4- one 16 1412-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7- 270-274 375.1(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one  2 1422-(3,4-dimethoxyphenyl)-9-methyl-7-[(3S)-3- 176-182 395.5methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4- one 22* 1432-(3,4-dimethoxyphenyl)-7-(1,2,3,6- 196-198 364.1tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin- 4-one 24* 1442-(3,4-dimethoxyphenyl)-7-(piperidin-4-yl)-4H- 214-217 366.4pyrido[1,2-a]pyrimidin-4-one  1 1452-(3-fluoro-4,5-dimethoxyphenyl)-7-(piperazin-1- ND 385.5yl)-4H-pyrido[1,2-a]pyrimidin-4-one  3 1462-(3,4-dimethoxyphenyl)-7-(4-hydroxypiperazin-1- 202-204 383.5yl)-4H-pyrido[1,2-a]pyrimidin-4-one  2 1472-(3,4-dimethoxyphenyl)-7-[(3S)-3- 156-158 395.4(dimethylamino)pyrrolidin-1-yl]-4H-pyrido[1,2- a]pyrimidin-4-one  2 1482-(3,4-dimethoxyphenyl)-7-[4- 158-161 409.1(dimethylamino)piperidin-1-yl]-4H-pyrido[1,2- a]pyrimidin-4-one 14 1492-(4-methoxy-3-methylphenyl)-7-(piperazin-1-yl)- 198-203 351.54H-pyrido[1,2-a]pyrimidin-4-one 14 1503-[4-oxo-7-(piperazin-1-yl)-4H-pyrido[1,2- 224-231 332.1a]pyrimidin-2-yl]benzonitrile 14 1512-methoxy-5-[4-oxo-7-(piperazin-1-yl)-4H- 191-197 362pyrido[1,2-a]pyrimidin-2-yl]benzonitrile 14 1522-(3-fluoro-4-hydroxyphenyl)-7-(piperazin-1-yl)-4H- 259-266 341.5pyrido[1,2-a]pyrimidin-4-one 20* 1532-(4-ethoxy-3-fluorophenyl)-7-(piperazin-1-yl)-4H- 180-186 369.1pyrido[1,2-a]pyrimidin-4-one 20 1542-[3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl]-7- 198-201 423.1(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 14 1552-(2-methyl-1,3-benzoxazol-5-yl)-7-(piperazin-1-yl)- 178-183 3624H-pyrido[1,2-a]pyrimidin-4-one 14 1562-(2-methyl-1,3-benzoxazol-5-yl)-7-[(3S)-3- ND 376.5methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4- one 14 1572-(3-fluoro-4-methylphenyl)-7-(piperazin-1-yl)-4H- 174-176 339.5pyrido[1,2-a]pyrimidin-4-one 14 1582-(3-fluoro-4-methylphenyl)-7-[(3S)-3- 175-178 353.5methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4- one  2 1597-[(3S)-3-aminopyrrolidin-1-yl]-2-(3,4- 148-151 367.1dimethoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one  2 1602-(3,4-dimethoxyphenyl)-9-methyl-7-(piperazin-1- 175 (S), 381.1yl)-4H-pyrido[1,2-a]pyrimidin-4-one 216-222 14 1617-(1,4-diazepan-1-yl)-2-(2-methyl-1,3-benzothiazol- 208-212 392.25-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 10 1627-[(3S)-3-methylpiperazin-1-yl]-2-(4-methyl-1,3- 225-230 342.1thiazol-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 10* 1632-(4-methyl-1,3-thiazol-2-yl)-7-(piperazin-1-yl)-4H- 142-147 328.2pyrido[1,2-a]pyrimidin-4-one 25* 1642-(3,4-dimethoxyphenyl)-7-(1-methylpiperidin-4-yl)- 181-183 380.14H-pyrido[1,2-a]pyrimidin-4-one  2 1652-(3,4-dimethoxyphenyl)-7-[(3S)-3-(propan-2- 169-172 409.1ylamino)pyrrolidin-1-yl]-4H-pyrido[1,2-a]pyrimidin- 4-one  1 1662-(3-fluoro-4-methoxyphenyl)-7-(4-methyl-1,4- 176-178 383.1diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 14 1672-(4-methoxy-3-nitrophenyl)-7-(piperazin-1-yl)-4H- 183-187 382.5pyrido[1,2-a]pyrimidin-4-one 14 1682-[3-fluoro-4-(methylsulfanyl)phenyl]-7-(piperazin- 174-176 371.11-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 15 1697-(4-methyl-1,4-diazepan-1-yl)-2-(2- 208-213 389.1methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2- a]pyrimidin-4-one  9*170 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4- 254-256 390.4methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4- one 14* 1712-(2-methyl-1,3-benzoxazol-6-yl)-7-(4- 178-183 376.5methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4- one 14 1727-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(2-methyl- 233-235 390.31,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4- one 17 1732-(5-fluoro-6-methoxypyridin-3-yl)-7-[(3S)-3- 175-180 370.5methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4- one 17 1747-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(5-fluoro- 160-165 384.56-methoxypyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin- 4-one 14 1757-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(2-methyl- 208-212 406.11,3-benzothiazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4- one 14 1762-(2-methyl-1,3-benzothiazol-5-yl)-7-(4- 214-218 392.1methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4- one 14 1772-(2-methyl-1,3-benzothiazol-5-yl)-7-(4-methyl-1,4- 165-170 406.1diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 14 1787-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]- 254-256 418.12-(2-methyl-1,3-benzothiazol-5-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 21*179 2-(4-methyl-1H-imidazol-1-yl)-7-(piperazin-1-yl)- 204-206 311.14H-pyrido[1,2-a]pyrimidin-4-one 21 1802-(4-methyl-1H-imidazol-1-yl)-7-[(3S)-3- 204-206 325.5methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4- one  2 1812-(3,4-dimethoxyphenyl)-7-{[2- 135-138 355(methylamino)ethyl]amino}-4H-pyrido[1,2- a]pyrimidin-4-one 17* 1822-(5-fluoro-6-methoxypyridin-3-yl)-7-(piperazin-1- 166-170 356.4yl)-4H-pyrido[1,2-a]pyrimidin-4-one 17 1832-(3,5-difluoro-4-methoxyphenyl)-7-(piperazin-1- 167-169 373.4yl)-4H-pyrido[1,2-a]pyrimidin-4-one 17 1842-(3,5-difluoro-4-methoxyphenyl)-7-[(3S)-3- 182-184 387.5methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4- one  2 1857-[4-(dimethylamino)piperidin-1-yl]-2-(3-fluoro-4- 196-201 397.1methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one  2 1862-(3-fluoro-4-methoxyphenyl)-7-(1,2,3,6- 182-184 352tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin- 4-one  2 1872-(3,4-dimethoxyphenyl)-7-(piperidin-4-ylamino)- ND 381.14H-pyrido[1,2-a]pyrimidin-4-one 23* 1882-(3,4-dimethoxyphenyl)-7-(1-methyl-1,2,3,6- 165-168 378.3tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin- 4-one 14 1892-(3-chloro-5-fluorophenyl)-7-[(3S)-3- 188-190 373methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4- one 14 1902-(3-chloro-5-fluorophenyl)-7-(piperazin-1-yl)-4H- 180-184 359.1pyrido[1,2-a]pyrimidin-4-one 18* 1917-[(3S)-3-methylpiperazin-1-yl]-2-(1-methyl-1H- 168-170 325.2pyrazol-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 18 1922-(1-methyl-1H-pyrazol-4-yl)-7-(piperazin-1-yl)-4H- ND 311.1pyrido[1,2-a]pyrimidin-4-one 14 1932-(2-methyl-1,3-benzoxazol-6-yl)-7-[(3R)-3- 175-177 376.5methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4- one 14 1947-(3,3-dimethylpiperazin-1-yl)-2-(2-methyl-1,3- 160-162 390.5benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 14 1957-(1,4-diazepan-1-yl)-2-(2-methyl-1,3-benzoxazol-6- 134-137 376.5yl)-4H-pyrido[1,2-a]pyrimidin-4-one 14 1962-(2-methyl-1,3-benzoxazol-6-yl)-7-(4-methyl-1,4- 146-150 390.5diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 14 1977-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]- 214-217 402.52-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 14 1987-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]- 194-199 402.52-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 14 1992-(4,5-dimethoxypyridin-2-yl)-7-(piperazin-1-yl)- 207-209 368.44H-pyrido[1,2-a]pyrimidin-4-one 33 2007-[3-(dimethylamino)pyrrolidin-1-yl]-2-(3-fluoro-4- 259-261 382.1methoxyphenyl)-4H-quinolizin-4-one 33 2017-(4-aminopiperidin-1-yl)-2-(3-fluoro-4- ND 368.2methoxyphenyl)-4H-quinolizin-4-one 14 2027-(4-ethylpiperazin-1-yl)-2-(2-methyl-1,3- 212-216 390.5benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 33  203a7-[4-(dimethylamino)piperidin-1-yl]-2-(3-fluoro-4- NI NImethoxyphenyl)-4H-quinolizin-4-one 23 2042-(3-fluoro-4-methoxyphenyl)-7-(1-methyl-1,2,3,6- 129-132 366tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin- 4-one  2 2057-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-2-(3- 187-192 383.1fluoro-4-methoxyphenyl)-4H-pyrido[1,2- a]pyrimidin-4-one  2 2067-[(3R,4R)-3-(dimethylamino)-4-hydroxypyrrolidin- 223-228 3991-yl]-2-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2- a]pyrimidin-4-one  2207 7-(4-aminopiperidin-1-yl)-2-(3-fluoro-4- 173-179 369.1methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one  2 2082-(3-fluoro-4-methoxyphenyl)-7-[4- 167-171 383.1(methylamino)piperidin-1-yl]-4H-pyrido[1,2- a]pyrimidin-4-one 16* 2092-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 282-288 379.4(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 16 2107-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(8-fluoro- 255-259 407.12-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 16211 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 262-266 407.6(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2- a]pyrimidin-4-one  2 2122-(3-fluoro-4-methoxyphenyl)-7-[(3aR,6aS)- 195-200 381.1hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4H- pyrido[1,2-a]pyrimidin-4-one 2 213 2-(3-fluoro-4-methoxyphenyl)-7-[(3aR,6aS)-5- 204-210 395.1methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 25 214 2-(3,4-dimethoxyphenyl)-7-[1-(2-145-148 410 hydroxyethyl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 14 215 2-(4-fluoro-3-methoxyphenyl)-7-[(3S)-3- 130-135369.2 methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4- one 14 2162-(4-fluoro-3-methoxyphenyl)-7-(piperazin-1-yl)- 170-172 355.24H-pyrido[1,2-a]pyrimidin-4-one 14 2172-(3,4-difluoro-5-methoxyphenyl)-7-[(3S)-3- 160-164 387.1methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4- one 14 2182-(3,4-difluoro-5-methoxyphenyl)-7-(piperazin-1- 155-160 373.1yl)-4H-pyrido[1,2-a]pyrimidin-4-one 14 2192-(2-methyl-1,3-benzothiazol-6-yl)-7-(piperazin-1- 218-220 378.1yl)-4H-pyrido[1,2-a]pyrimidin-4-one 29* 2207-(3-fluoro-4-methoxyphenyl)-2-(piperazin-1-yl)- 202-206 3554H-pyrido[1,2-a]pyrimidin-4-one 14 2212-(2-methyl-1,3-benzothiazol-6-yl)-7-[(3S)-3- 214-216 392.1methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4- one  2 2222-(3-fluoro-4-methoxyphenyl)-7-[(3S)-3- 208-216 369.1(methylamino)pyrrolidin-1-yl]-4H-pyrido[1,2- a]pyrimidin-4-one  2 2232-(3-fluoro-4-methoxyphenyl)-7-{4- 163-170 397.1[(methylamino)methyl]piperidin-1-yl}-4H- pyrido[1,2-a]pyrimidin-4-one  2224 7-[(3S)-3-aminopyrrolidin-1-yl]-2-(3-fluoro-4- 193-198 355methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one  2 2252-(3-fluoro-4-methoxyphenyl)-7-{[(3R)-1- 197-202 369.1methylpyrrolidin-3-yl]amino}-4H-pyrido[1,2- a]pyrimidin-4-one  2 2267-{4-[(dimethylamino)methyl]piperidin-1-yl}-2-(3- 178-185 411.1fluoro-4-methoxyphenyl)-4H-pyrido[1,2- a]pyrimidin-4-one 14 2272-(6-methoxypyridin-2-yl)-7-(piperazin-1-yl)-4H- 214-218 338.1pyrido[1,2-a]pyrimidin-4-one 14 2287-(piperazin-1-yl)-2-(pyridin-3-yl)-4H-pyrido[1,2- 175-178 308a]pyrimidin-4-one 14 2292-(5-methoxypyridin-3-yl)-7-(piperazin-1-yl)-4H- 192-195 338pyrido[1,2-a]pyrimidin-4-one 14 2303-fluoro-5-{7-[(3S)-3-methylpiperazin-1-yl]-4-oxo- 185-188 364.24H-pyrido[1,2-a]pyrimidin-2-yl}benzonitrile 14 2313-fluoro-5-[4-oxo-7-(piperazin-1-yl)-4H-pyrido[1,2- 238-244 350.1a]pyrimidin-2-yl]benzonitrile  2 2322-(3-fluoro-4-methoxyphenyl)-7-[(3′S,4′S)-4′- 226-232 425.1hydroxy-1,3′-bipyrrolidin-1′-yl]-4H-pyrido[1,2- a]pyrimidin-4-one  2 2332-(3-fluoro-4-methoxyphenyl)-7-(methyl[(3R)- 143-147 369.1pyrrolidin-3-yl]amino}-4H-pyrido[1,2-a]pyrimidin- 4-one 14 2347-[(3S)-3,4-dimethylpiperazin-1-yl]-2-(2-methyl-1,3- 205-209 390.6benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 27 2352-(3,4-dimethoxyphenyl)-7-[(1-methylpiperidin-4- ND 396.2yl)oxy]-4H-pyrido[1,2-a]pyrimidin-4-one 27 2362-(3,4-dimethoxyphenyl)-7-[(3S)-pyrrolidin-3- 164-166 368.1yloxy]-4H-pyrido[1,2-a]pyrimidin-4-one 27* 2372-(3,4-dimethoxyphenyl)-7-(piperidin-4-yloxy)-4H- 221-224 382.2pyrido[1,2-a]pyrimidin-4-one  2 2387-(1,4-diazepan-1-yl)-2-(3,4-dimethoxyphenyl)-9- 160-177 395.5methyl-4H-pyrido[1,2-a]pyrimidin-4-one  2* 2392-(3-fluoro-4-methoxyphenyl)-7-{methyl[(3R)-1- 143-149 383.5methylpyrrolidin-3-yl]amino}-4H-pyrido[1,2- a]pyrimidin-4-one 14 2407-[4-(dimethylamino)piperidin-1-yl]-2-(2-methyl- 206-210 404.51,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4- one 14 2417-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-2-(2- 189-193 390.5methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 14 2427-(4-aminopiperidin-1-yl)-2-(2-methyl-1,3- ND 376.2benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 14 2437-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)- ND 388.3yl]-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 14244 7-[(3R)-3,4-dimethylpiperazin-1-yl]-2-(2-methyl- 181-187 390.51,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4- one 34* 2452-(3,4-dimethoxyphenyl)-7-(1,2,3,6- 174-176 363.2tetrahydropyridin-4-yl)-4H-quinolizin-4-one  2 2462-(3-fluoro-4-methoxyphenyl)-7-[(3aR,6aR)-1- 205-209 395.2methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one  2 2472-(3,4-dimethoxyphenyl)-9-methyl-7-(1,2,3,6- 186-191 378.2tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin- 4-one 23 2482-(3,4-dimethoxyphenyl)-7-[1-(2-hydroxyethyl)- 134-137 408.21,2,3,6-tetrahydropyridin-4-yl]-4H-pyrido[1,2- a]pyrimidin-4-one 35* 2492-(3,4-dimethoxyphenyl)-7-(1-methyl-1,2,3,6- 194-196 377.2tetrahydropyridin-4-yl)-4H-quinolizin-4-one 24 2502-(3,4-dimethoxyphenyl)-9-methyl-7-(piperidin-4- 176-181 380.3yl)-4H-pyrido[1,2-a]pyrimidin-4-one 23 2512-(3,4-dimethoxyphenyl)-9-methyl-7-(1-methyl- 187-196 392.21,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 25 2522-(3,4-dimethoxyphenyl)-9-methyl-7-(1- 170-174 394.2methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4- one 14 2537-(1,4-diazepan-1-yl)-2-(2-methyl-1,3-benzothiazol- 205-207 392.26-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 14 2542-(2-methyl-1,3-benzothiazol-6-yl)-7-(4-methyl-1,4- 158-160 406.1diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 14 2557-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]- 250-260 418.12-(2-methyl-1,3-benzothiazol-6-yl)-4H-pyrido[1,2- (DR) a]pyrimidin-4-one14 256 2-(2-methyl-1,3-benzothiazol-6-yl)-7-(4- 230-234 392.1methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4- one  2 2572-(3,4-dimethoxyphenyl)-7-[(3aR,6aS)- 215 (S), 407.3hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-9-methyl- 246-2514H-pyrido[1,2-a]pyrimidin-4-one  9 2587-[(3S)-3,4-dimethylpiperazin-1-yl]-2-(4,6- 220-223 404.3dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H- pyrido[1,2-a]pyrimidin-4-one  9259 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7- 254-260 418.3[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]-4H- pyrido[1,2-a]pyrimidin-4-one 2 260 2-(3,4-dimethoxyphenyl)-9-methyl-7-[(3aR,6aS)-5- 212-218 421.2methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one  2 261 2-(3,4-dimethoxyphenyl)-7-[4-167-171 423.3 (dimethylamino)piperidin-1-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one 22 2627-[(1R,5S)-8-azabicyclo[3.2.1]oct-2-en-3-yl]-2-(3,4- 191-194 390.2dimethoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one 26* 2632-(3,4-dimethoxyphenyl)-7-(1,2,5,6- 146-150 364.2tetrahydropyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin- 4-one 14 2647-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-2-(2- 203-207 390.2methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 14 2652-(2-ethyl-1,3-benzoxazol-6-yl)-7-(piperazin-1-yl)- 170-175 376.24H-pyrido[1,2-a]pyrimidin-4-one 14 2662-(2-ethyl-1,3-benzoxazol-6-yl)-7-[(3S)-3- 168-170 390.2methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4- one 14 2672-(2-methyl-1,3-benzoxazol-6-yl)-7-[(3aR,6aS)-5- 200-204 402.2methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 29 2687-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2- 308 (D) 379.2(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 16 2692-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 283-286 393.3(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin- 4-one 16 2702-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- ND 393.3[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2- a]pyrimidin-4-one 16 2712-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 270-274 419.3[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 16 2722-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 277-280 419.2[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 16 2737-(4-aminopiperidin-1-yl)-2-(8-fluoro-2- ND 393.3methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 16274 7-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-2-(8- 300 (D) 407.3fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 16 2757-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-2-(8- 294-297 407.3fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 30* 2762-(4-aminopiperidin-1-yl)-7-(3-fluoro-4- 268-283 369.3methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one 30 2772-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-7-(3- 167-170 383.2fluoro-4-methoxyphenyl)-4H-pyrido[1,2- a]pyrimidin-4-one 30 2782-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-7-(3- 167-169 383.2fluoro-4-methoxyphenyl)-4H-pyrido[1,2- a]pyrimidin-4-one  2 2792-(3-fluoro-4-methoxyphenyl)-7-[(3aR,6aS)-5-(2- 180-186 425.3hydroxyethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one  2 2802-(3-fluoro-4-methoxyphenyl)-7-[(3aS,6aS)-1- 207-211 395.3methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one  2 2812-(3-fluoro-4-methoxyphenyl)-7-[(3aR,6aS)-5- 189-192 423.3(propan-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one  2 2827-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-2-(3- 188-191 383.3fluoro-4-methoxyphenyl)-4H-pyrido[1,2- a]pyrimidin-4-one 14 2837-(3,3-dimethylpiperazin-1-yl)-2-(2-methyl-1,3- 200-202 406.3benzothiazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 14 2847-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]- 254-256 418.22-(2-methyl-1,3-benzothiazol-6-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 14285 7-[4-(dimethylamino)piperidin-1-yl]-2-(2-methyl- ND 420.21,3-benzothiazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4- one 27 2862-(2-methyl-1,3-benzothiazol-6-yl)-7-(piperidin-4- 218-220 393.1yloxy)-4H-pyrido[1,2-a]pyrimidin-4-one 16 2872-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 245-251 395.2(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 16 2882-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 289-295 423.1[(3R,5S)-3,5-dimethylpiperazin-1-yl]-4H-pyrido[1,2- a]pyrimidin-4-one 16289 2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 239-244 423.2(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 16 2902-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 236-239 409.1[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2- a]pyrimidin-4-one 16 2912-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 236-239 409.1[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2- a]pyrimidin-4-one 16 2922-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 274-280 435.2[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 16 2932-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 269-275 435.2[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 46* 2947-(3-fluoro-4-methoxyphenyl)-2-(1,2,3,6- 188-192 352.1tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin- 4-one 39 2957-[(3S)-3,4-dimethylpiperazin-1-yl]-2-(8-fluoro-2- 269-275 407.3methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 39296 7-[(3R)-3,4-dimethylpiperazin-1-yl]-2-(8-fluoro-2- 279-282 407.3methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 39297 7-[4-(dimethylamino)piperidin-1-yl]-2-(8-fluoro-2- 250-257 421.3methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 39298 2-[4-(dimethylamino)piperidin-1-yl]-7-(3-fluoro-4- 157-160 397.2methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one 37 2992-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-7- 177-180 377.2(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 23 3002-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-7-(1- 178-181 391.3methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H- pyrido[1,2-a]pyrimidin-4-one 2 301 2-(3-fluoro-4-methoxyphenyl)-7-[(4aR,7aR)- 194-201 395.2octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 37 3022-(2-methyl-1,3-benzoxazol-6-yl)-7-(1,2,3,6- ND 359.2tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin- 4-one 23 3032-(2-methyl-1,3-benzoxazol-6-yl)-7-(1-methyl- 132-135 373.31,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 23 3047-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(2- 128-131 387.3methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 36 3052-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-7- 184-186 380.3(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 36* 3062-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-7-[(3S)- 207-209 394.33-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin- 4-one 39 3077-[(3S)-3,4-dimethylpiperazin-1-yl]-2-(4-fluoro-2- 194-196 408.3methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 36 3082-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-7-(4- 219-221 394.1methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4- one 36 3097-(4-ethylpiperazin-1-yl)-2-(4-fluoro-2-methyl-1,3- 212-214 408.2benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 36 3102-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-7-(4- 175-178 422.1propylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4- one  2 3117-[(3aR,6aS)-5-ethylhexahydropyrrolo[3,4-c]pyrrol- 157-167 409.12(1H)-yl]-2-(3-fluoro-4-methoxyphenyl)-4H- pyrido[1,2-a]pyrimidin-4-one22 312 2-(3-fluoro-4-methoxyphenyl)-9-methyl-7-(1,2,3,6- 211-215 366.1tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin- 4-one  2 3132-(3-fluoro-4-methoxyphenyl)-7-[(4aR,7aR)-1- 223-227 409.1methyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-4H-pyrido[1,2-a]pyrimidin-4-one  2 3142-(3,4-dimethoxyphenyl)-9-methyl-7-[(3R)-3- 177-184 395.2methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4- one 23 3152-(3-fluoro-4-methoxyphenyl)-9-methyl-7-(1- 184-190 380.1methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H- pyrido[1,2-a]pyrimidin-4-one24 316 7-(3-fluoro-4-methoxyphenyl)-2-(piperidin-4-yl)- 278-281 354.14H-pyrido[1,2-a]pyrimidin-4-one 25 3177-(3-fluoro-4-methoxyphenyl)-2-(1-methylpiperidin- 202-205 368.14-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 23 3187-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(4- 151-154 405.2fluoro-2-methyl-1,3-benzoxazol-6-yl)-4H- pyrido[1,2-a]pyrimidin-4-one 23319 2-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-7-(1- 159-162 419.3propyl-1,2,3,6-tetrahydropyridin-4-yl)-4H- pyrido[1,2-a]pyrimidin-4-one25 320 2-(3,4-dimethoxyphenyl)-7-[(1R,5S)-8-methyl-8- ND 406.2azabicyclo[3.2.1]oct-3-yl]-4H-pyrido[1,2- a]pyrimidin-4-one  2 3212-(3,4-dimethoxyphenyl)-7-[(2R)-2-methylpiperazin- ND 381.11-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 54* 3222-(2-methyl-1,3-benzoxazol-6-yl)-7-[(3S)-3- 115-117 375.3methylpiperazin-1-yl]-4H-quinolizin-4-one 54 3232-(2-methyl-1,3-benzoxazol-6-yl)-7-(4- ND 375.1methylpiperazin-1-yl)-4H-quinolizin-4-one 39 3247-[(3S)-4-ethyl-3-methylpiperazin-1-yl]-2-(2- 288-290 403.2methyl-1,3-benzoxazol-6-yl)-4H-quinolizin-4-one 39 3257-[(3S)-3,4-dimethylpiperazin-1-yl]-2-(2-methyl-1,3- >300 389.2benzoxazol-6-yl)-4H-quinolizin-4-one 45 3267-(4-aminopiperidin-1-yl)-2-(2-methyl-1,3- 288-290 375.2benzoxazol-6-yl)-4H-quinolizin-4-one  2 3272-(3-fluoro-4-methoxyphenyl)-9-methyl-7-[(3S)-3- 198-202 383.1methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4- one  2 3287-[4-(dimethylamino)piperidin-1-yl]-2-(3-fluoro-4- 141-145 411.2methoxyphenyl)-9-methyl-4H-pyrido[1,2- a]pyrimidin-4-one 25 3292-(3-fluoro-4-methoxyphenyl)-9-methyl-7-(1- 198-203 382.2methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4- one 53 3307-[4-(cyclopropylamino)piperidin-1-yl]-2-(3,4- 141 (S), 435.3dimethoxyphenyl)-9-methyl-4H-pyrido[1,2- 158-161 a]pyrimidin-4-one 39331 2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 258-262 423.2[(3S)-3,4-dimethylpiperazin-1-yl]-4H-pyrido[1,2- a]pyrimidin-4-one  2332 2-(3,4-dimethoxyphenyl)-7-[(3R,5S)-3,5- 225-233 409.3dimethylpiperazin-1-yl]-9-methyl-4H-pyrido[1,2- a]pyrimidin-4-one  2 3332-(3,4-dimethoxyphenyl)-7-[(3R)-3,4- 148 (S), 409.3dimethylpiperazin-1-yl]-9-methyl-4H-pyrido[1,2- 168-177a]pyrimidin-4-one  9 3342-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4- 169-171 404.4methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2- a]pyrimidin-4-one  9 3352-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7- ND 390.4[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2- a]pyrimidin-4-one  9 3362-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7- 215-218 416.3[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one  9 3372-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7- 228-230 416.4[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one  9 3382-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4- 251-253 404.4ethylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4- one  9 3397-[4-(dimethylamino)piperidin-1-yl]-2-(4,6- 208-210 418.4dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H- pyrido[1,2-a]pyrimidin-4-one  9340 7-(3,3-dimethylpiperazin-1-yl)-2-(4,6- 195-197 404.4dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H- pyrido[1,2-a]pyrimidin-4-one  9341 7-(4-cyclopropylpiperazin-1-yl)-2-(4,6- 189-192 416.4dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H- pyrido[1,2-a]pyrimidin-4-one38* 342 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7- 207-210 373.3(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 39 3432-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7- ND 418.4[(3R)-4-ethyl-3-methylpiperazin-1-yl]-4H- pyrido[1,2-a]pyrimidin-4-one 2 344 2-(3,4-dimethoxyphenyl)-9-methyl-7-(4- 191-198 395.3methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4- one  2 3452-(3,4-dimethoxyphenyl)-7-[4- 146-150 437.3(dimethylamino)piperidin-1-yl]-9-ethyl-4H- pyrido[1,2-a]pyrimidin-4-one23 346 2-(3,4-dimethoxyphenyl)-7-[1-(2-hydroxyethyl)- 169-179 422.31,2,3,6-tetrahydropyridin-4-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one 14 3477-[4-(dimethylamino)piperidin-1-yl]-2-(2-methyl- 218-220 420.21,3-benzothiazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4- one 45 3487-(4-aminopiperidin-1-yl)-2-(2-methyl-1,3- 190-192 392.1benzothiazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 45 3497-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)- ND 404.1yl]-2-(2-methyl-1,3-benzothiazol-5-yl)-4H- pyrido[1,2-a]pyrimidin-4-one23 350 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1- 193-197 387.4methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H- pyrido[1,2-a]pyrimidin-4-one23 351 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1- 202-204 401.4ethyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2- a]pyrimidin-4-one23 352 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1- 191-193 415.5propyl-1,2,3,6-tetrahydropyridin-4-yl)-4H- pyrido[1,2-a]pyrimidin-4-one49* 353 2-(3,4-dimethoxyphenyl)-7-(1,2,3,6- ND 365.1tetrahydropyridin-4-yl)-4H-pyrimido[1,2- a]pyrimidin-4-one 23 3547-(1-cyclopropyl-1,2,3,6-tetrahydropyridin-4-yl)-2- ND 413.4(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 23 3552-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1- 186-189 415.4(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 23 3567-(1-cyclobutyl-1,2,3,6-tetrahydropyridin-4-yl)-2- 191-193 427.4(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 23 3572-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1- ND 429.3(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 53 3582-(3,4-dimethoxyphenyl)-9-methyl-7-[4- ND 409.3(methylamino)piperidin-1-yl]-4H-pyrido[1,2- a]pyrimidin-4-one 53 3592-(3,4-dimethoxyphenyl)-7-[4- ND 423.4(ethylamino)piperidin-1-yl]-9-methyl-4H-pyrido[1,2- a]pyrimidin-4-one  2360 2-(3,4-dimethoxyphenyl)-8-methyl-7-(piperazin-1- 161-169 381.3yl)-4H-pyrido[1,2-a]pyrimidin-4-one 39 3612-(3,4-dimethoxyphenyl)-7-[4-(propan-2- ND 423.3ylamino)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin- 4-one 23 3627-(1-cyclobutyl-1,2,3,6-tetrahydropyridin-4-yl)-2- 152-154 418.3(3,4-dimethoxyphenyl)-4H-pyrido[1,2-a]pyrimidin- 4-one 23 3632-(3,4-dimethoxyphenyl)-7-[1-(propan-2-yl)-1,2,3,6- 116-118 406.3tetrahydropyridin-4-yl]-4H-pyrido[1,2-a]pyrimidin- 4-one 23 3642-(3,4-dimethoxyphenyl)-7-[1-(oxetan-3-yl)-1,2,3,6- 178-180 420.3tetrahydropyridin-4-yl]-4H-pyrido[1,2-a]pyrimidin- 4-one 23 3652-(3,4-dimethoxyphenyl)-7-(1-propyl-1,2,3,6- 158-160 406.2tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin- 4-one 22 3662-(3,4-dimethoxyphenyl)-7-[4- 232-235 392.3(methylamino)cyclohex-1-en-1-yl]-4H-pyrido[1,2- a]pyrimidin-4-one 23 3672-(3,4-dimethoxyphenyl)-7-[4- 162-164 406.2(dimethylamino)cyclohex-1-en-1-yl]-4H-pyrido[1,2- a]pyrimidin-4-one 23368 2-(3,4-dimethoxyphenyl)-7-{4- 132-134 420.4[ethyl(methyl)amino]cyclohex-1-en-1-yl}-4H- pyrido[1,2-a]pyrimidin-4-one23 369 2-(3,4-dimethoxyphenyl)-7-{4- 116-118 434.4[methyl(propyl)amino]cyclohex-1-en-1-yl}-4H-pyrido[1,2-a]pyrimidin-4-one 23 3702-(3,4-dimethoxyphenyl)-7-(1-ethyl-1,2,3,6- 170-172 392.3tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin- 4-one 46 3717-(3,4-dimethoxyphenyl)-2-(1,2,3,6- 172-178 364.3tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin- 4-one 46 3727-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2- ND 376.2(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 16 3732-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 260-264 421.3[4-(propan-2-yl)piperazin-1-yl]-4H-pyrido[1,2- a]pyrimidin-4-one 16 3742-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 287-292 437.4[4-(propan-2-yl)piperazin-1-yl]-4H-pyrido[1,2- a]pyrimidin-4-one 46 3757-(2-methylimidazo[1,2-a]pyridin-6-yl)-2-(1,2,3,6- 197-201 358.2tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin- 4-one 23 3767-(2-methylimidazo[1,2-a]pyridin-6-yl)-2-(1-methyl- 203-207 372.21,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 23 3777-(3,4-dimethoxyphenyl)-2-(1-methyl-1,2,3,6- 149-152 378.3tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin- 4-one 23 3782-(3,4-dimethoxyphenyl)-9-methyl-7-(1-propyl- 171-177 420.31,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 23 3797-(1-cyclobutyl-1,2,3,6-tetrahydropyridin-4-yl)-2- 167-178 432.3(3,4-dimethoxyphenyl)-9-methyl-4H-pyrido[1,2- a]pyrimidin-4-one 55  380a2-(2-methyl-1,3-benzothiazol-6-yl)-7-(piperidin-4- NI NIyl)-4H-pyrimido[1,2-b]pyridazin-4-one 45 3817-(4-aminopiperidin-1-yl)-2-(2-methyl-1,3- 190-194 392.2benzothiazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 45 3827-(3-aminopyrrolidin-1-yl)-2-(2-methyl-1,3- 196-200 378.2benzothiazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 14 3837-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-2-(2- 235-240 406.3methyl-1,3-benzothiazol-6-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 37 3842-(2-methyl-1,3-benzothiazol-6-yl)-7-(1,2,3,6- 124-126 375.2tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin- 4-one 16 3852-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 258-262 437.5[4-(2-methoxyethyl)piperazin-1-yl]-4H-pyrido[1,2- a]pyrimidin-4-one 23386 2-(3,4-dimethoxyphenyl)-9-methyl-7-[1-(oxetan-3- 180-195 434.3yl)-1,2,3,6-tetrahydropyridin-4-yl]-4H-pyrido[1,2- (DR)a]pyrimidin-4-one 23 3872-(3,4-dimethoxyphenyl)-9-methyl-7-[1-(propan-2- 153-163 420.4yl)-1,2,3,6-tetrahydropyridin-4-yl]-4H-pyrido[1,2- a]pyrimidin-4-one 23388 2-(3,4-dimethoxyphenyl)-7-(1-ethyl-1,2,3,6- ND 406.4tetrahydropyridin-4-yl)-9-methyl-4H-pyrido[1,2- a]pyrimidin-4-one 22 3892-(3,4-dimethoxyphenyl)-8-methyl-7-(1,2,3,6- 175 (D) 378.3tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin- 4-one 23 3907-(1-cyclopropyl-1,2,3,6-tetrahydropyridin-4-yl)-2- 180-189 418.4(3,4-dimethoxyphenyl)-9-methyl-4H-pyrido[1,2- a]pyrimidin-4-one 23 3912-(3,4-dimethoxyphenyl)-8-methyl-7-(1-methyl- 174-178 392.41,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 23 3922-(2-methyl-1,3-benzothiazol-6-yl)-7-(1-methyl- 170-172 389.21,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 23 3937-[1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyridin-4- 178-180 419.2yl]-2-(2-methyl-1,3-benzothiazol-6-yl)-4H- pyrido[1,2-a]pyrimidin-4-one23 394 2-(2-methyl-1,3-benzothiazol-6-yl)-7-[1-(propan-2- 168-170 417.2yl)-1,2,3,6-tetrahydropyridin-4-yl]-4H-pyrido[1,2- a]pyrimidin-4-one 23395 7-(1-cyclopropyl-1,2,3,6-tetrahydropyridin-4-yl)-2- 158-160 415.3(2-methyl-1,3-benzothiazol-6-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 23 3967-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(2- 128-130 403.2methyl-1,3-benzothiazol-6-yl)-4H-pyrido[1,2- (DR) a]pyrimidin-4-one 39397 7-[(3R)-3,4-dimethylpiperazin-1-yl]-2-(4,6- 247-249 404.5dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H- pyrido[1,2-a]pyrimidin-4-one56* 398 2-(3,4-dimethoxyphenyl)-7-(1,2,3,6- 195-200 365.3tetrahydropyridin-4-yl)-4H-pyrimido[1,2- b]pyridazin-4-one  9 3997-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-(4,6- 218-221 388.3dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H- pyrido[1,2-a]pyrimidin-4-one 39400 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7- 188-191 402.3[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 39 4012-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7- 175-177 416.4[(1S,4S?)-5-ethyl-2,5-diazabicyclo[2.2.1]hept-2-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 57* 4022-(3,4-dimethoxyphenyl)-7-(1,2,3,6- 205-208 365.4tetrahydropyridin-4-yl)-4H-pyrazino[1,2- a]pyrimidin-4-one 24 4032-(3-fluoro-4-methoxyphenyl)-7-(piperidin-4-yl)- 122-125 354.34H-pyrido[1,2-a]pyrimidin-4-one 25 4042-(3,4-dimethoxyphenyl)-7-(1-ethylpiperidin-4-yl)- 155-157 394.44H-pyrido[1,2-a]pyrimidin-4-one 24 405 2-(3,4-dimethoxyphenyl)-7-[cis-4- 156-158 394.4 (methylamino)cyclohexyl]-4H-pyrido[1,2-a]pyrimidin-4-one 24 406 2-(3,4-dimethoxyphenyl)-7-(piperidin-3-yl)-4H-126-129 366.3 pyrido[1,2-a]pyrimidin-4-one 53* 4072-(3,4-dimethoxyphenyl)-9-methyl-7-[4- 178-184 437.5(propylamino)piperidin-1-yl]-4H-pyrido[1,2- a]pyrimidin-4-one 22 4082-(3,4-dimethoxyphenyl)-9-ethyl-7-(1,2,3,6- 171-177 392.4tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin- 4-one 24 4097-(2-methylimidazo[1,2-a]pyridin-6-yl)-2-(piperidin- 255-258 360.44-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 24 4107-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2- 295-298 378.4(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 23 4117-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2- 218-222 390.4(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 16 4127-(4-cyclopropylpiperazin-1-yl)-2-(8-fluoro-2- 254-258 419.4methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 57 413a 2-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7- NI NI(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrazino[1,2- a]pyrimidin-4-one  2414 2-(3,4-dimethoxyphenyl)-7-[(8aR)- ND 421.4hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one 23 4152-(3,4-dimethoxyphenyl)-9-ethyl-7-(1-methyl- 177-182 406.41,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 53 4162-(3,4-dimethoxyphenyl)-9-methyl-7-[4-(propan-2- 178-183 437.5ylamino)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin- 4-one  2 4172-(3,4-dimethoxyphenyl)-7-[(8aS)- 183-189 421.4hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one 23 4182-(3,4-dimethoxyphenyl)-9-ethyl-7-(1-ethyl-1,2,3,6- 148-153 420.5tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin- 4-one 53 4192-(3,4-dimethoxyphenyl)-9-methyl-7-[4-(morpholin- 219-224 465.54-yl)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4- one  9 4202-(6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7- 202-204 362.2(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 57 4212-(2-methyl-1,3-benzoxazol-6-yl)-7-(1,2,3,6- ND 360.1tetrahydropyridin-4-yl)-4H-pyrazino[1,2- a]pyrimidin-4-one hydrochloride(1:1) 23 422 2-(2-methyl-1,3-benzoxazol-6-yl)-7-(1-methyl- 240-242 374.3l,2,3,6-tetrahydropyridin-4-yl)-4H-pyrazino[1,2- a]pyrimidin-4-one 23423 7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(2- 225-227 388.4methyl-1,3-benzoxazol-6-yl)-4H-pyrazino[1,2- a]pyrimidin-4-one 24 4242-(2-methyl-1,3-benzothiazol-6-yl)-7-(piperidin-4- 222-224 377.1yl)-4H-pyrido[1,2-a]pyrimidin-4-one  9 4252-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4- 215-218 444.4(pyrrolidin-1-yl)piperidin-1-yl]-4H-pyrido[1,2- a]pyrimidin-4-one  9 4267-(1,4′-bipiperidin-1′-yl)-2-(4,6- 236-238 458.4dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H- pyrido[1,2-a]pyrimidin-4-one  9427 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(4- 198-200 473.5methylpiperazin-1-yl)piperidin-1-yl]-4H-pyrido[1,2- a]pyrimidin-4-one  9428 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4- 192-195 460.4(morpholin-4-yl)piperidin-1-yl]-4H-pyrido[1,2- a]pyrimidin-4-one 37 4292-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1,2,3,6- 206-208 358.4tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin- 4-one 23 4302-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1-methyl- 137-140 372.21,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 23 4317-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(2- 220-223 386.4methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 14432 7-[4-(dimethylamino)piperidin-1-yl]-2-(2- 204-206 403.4methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 53433 2-(3,4-dimethoxyphenyl)-7-{4-[(2- 185-193 439.4hydroxyethyl)amino]piperidin-1-yl}-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one 25 4342-(3,4-dimethoxyphenyl)-9-ethyl-7-(1- 146 (S), 408.4methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4- 166-169 one 53 4357-[4-(diethylamino)piperidin-1-yl]-2-(3,4- 149-155 451.5dimethoxyphenyl)-9-methyl-4H-pyrido[1,2- a]pyrimidin-4-one 25 4362-(3,4-dimethoxyphenyl)-9-ethyl-7-(1- 157-162 422.4ethylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4- one 14 4372-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-[4- 230-232 429.4(pyrrolidin-1-yl)piperidin-1-yl]-4H-pyrido[1,2- a]pyrimidin-4-one 51 4382-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperidin- 298-300 360.14-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 25 4392-(2-methyl-1,3-benzothiazol-6-yl)-7-(1- 240-242 391.4methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4- one  9 4407-(4-methylpiperazin-1-yl)-2-(6-methylpyrazolo[1,5- 230-240 376.2a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (DR)  9 4417-[(3S)-3-methylpiperazin-1-yl]-2-(6- 235-240 376.2methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2- (DR) a]pyrimidin-4-one 9 442 7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(6- 258-260 390.3methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 37*443 2-(1-methyl-1H-indazol-5-yl)-7-(1,2,3,6- 200-203 358.2tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin- 4-one 37 4442-[6-(dimethylamino)pyridin-3-yl]-7-(1,2,3,6- 255-257 348.4tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin- 4-one 37 4457-[4-(diethylamino)piperidin-1-yl]-2-(2- 208-210 431.4methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 53446 2-(3,4-dimethoxyphenyl)-7-{4-[(2- 164-171 453.5hydroxyethyl)(methyl)amino]piperidin-1-yl}-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one  2 4472-(3,4-dimethoxyphenyl)-9-ethyl-7-[(3R)-3- 140-147 409.2methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4- one 25 4482-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1- 218-220 374.3methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4- one 23 4492-(1-methyl-1H-indazol-5-yl)-7-(1-methyl-1,2,3,6- 148-150 372.3tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin- 4-one 23 4502-[6-(dimethylamino)pyridin-3-yl]-7-(1-methyl- 214-216 362.41,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2- a]pyrimidin-4-one  9 4517-[4-(diethylamino)piperidin-1-yl]-2-(4,6- 232-235 446.5dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H- pyrido[1,2-a]pyrimidin-4-one 24452 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7- ND 375.4(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 25 4532-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1- 220-222 389.3methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4- one 25 4542-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1- 170-172 403.3ethylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4- one  2 4552-(3,4-dimethoxyphenyl)-9-ethyl-7-[(8aR)- 180-184 435.3hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 53 456 2-(3,4-dimethoxyphenyl)-7-{4-[(2-178-182 453.3 methoxyethyl)amino]piperidin-1-yl}-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one  9 4572-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9- 262-271 404.2methyl-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2- a]pyrimidin-4-one  2458 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7- 244-256 430.3[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one  2 4597-[4-(dimethylamino)piperidin-1-yl]-2-(4,6- 231-241 432.4dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one 25 4607-(2-methylimidazo[1,2-a]pyridin-6-yl)-2-(1- 227-230 374.3methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4- one 25 4617-(2-methylimidazo[1,2-a]pyridin-6-yl)-2-[1- 215-218 402.3(propan-2-yl)piperidin-4-yl]-4H-pyrido[1,2- a]pyrimidin-4-one 25 4627-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2- 235-238 392.3(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin- 4-one 23 4637-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(1- 172-174 386.3methyl-1H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin- 4-one 23 4642-(1-methyl-1H-indazol-5-yl)-7-(1-propyl-1,2,3,6- 152-154 400.4tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin- 4-one 24 4652-[6-(dimethylamino)pyridin-3-yl]-7-(piperidin-4- 208-210 350.3yl)-4H-pyrido[1,2-a]pyrimidin-4-one  9 4667-(4-ethylpiperazin-1-yl)-2-(6-methylpyrazolo[1,5- 220-230 390.3a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (DR)  9 4677-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]- 240-250 402.32-(6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H- (DR)pyrido[1,2-a]pyrimidin-4-one  9 4687-[4-(dimethylamino)piperidin-1-yl]-2-(6- 240-242 404.3methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2- a]pyrimidin-4-one  9469 7-[4-(2-hydroxyethyl)piperazin-1-yl]-2-(6- 254-256 406.3methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 25470 2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1- 159-161 402.4propylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4- one 23 4717-[1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyridin-4- ND 402.3yl]-2-(1-methyl-1H-indazol-5-yl)-4H-pyrido[1,2- a]pyrimidin-4-one  9 4727-[(3R)-3-methylpiperazin-1-yl]-2-(6- 240-244 376.2methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 38473 2-(6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1,2,3,6- 260-265 359.2tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin- (DR) 4-one 37 4742-(2-methyl-2H-indazol-5-yl)-7-(1,2,3,6- 239-241 358.4tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin- 4-one 37 4752-(1-methyl-1H-indazol-5-yl)-7-(1-methylpiperidin- 216-218 374.44-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 25 4762-(2-methyl-2H-indazol-5-yl)-7-(1-methyl-1,2,3,6- 226-228 372.3tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin- 4-one 23 4777-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(2- 198-200 386.4methyl-2H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin- 4-one 23 4787-(1-ethylpiperidin-4-yl)-2-(2-methylimidazo[1,2- 190-192 388.4a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 23 4792-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-[1- 220-222 415.3(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]-4H-pyrazino[1,2-a]pyrimidin-4-one 22 4802-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9- >300 387.4methyl-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 23 4812-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9- ND 401.4methyl-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 23 4822-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1- ND 415.5ethyl-1,2,3,6-tetrahydropyridin-4-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one 23 4837-(1-cyclopropyl-1,2,3,6-tetrahydropyridin-4-yl)-2- ND 427.4(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one 23 4842-(6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1- 126-128 373.2methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H- (DR)pyrido[1,2-a]pyrimidin-4-one 23 4857-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(6- ND 387.3methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 50*486 2-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-(piperazin- 198-200 376.31-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 50 4872-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-(4- 256-258 390.2methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4- one 50 4882-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-[(3S)-3- 202-204 390.3methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4- one 14 4892-(1-methyl-1H-indazol-5-yl)-7-(4-methylpiperazin- 194-196 375.31-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 14 4902-(1-methyl-1H-indazol-5-yl)-7-(piperazin-1-yl)-4H- 206-208 361.3pyrido[1,2-a]pyrimidin-4-one 14 4917-[4-(dimethylamino)piperidin-1-yl]-2-(1-methyl- 209-212 403.51H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 14 4927-(4-methyl-1,4-diazepan-1-yl)-2-(1-methyl-1H- ND 389.4indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 23 4937-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(2- 205-207 388.4methyl-1,3-benzoxazol-6-yl)-4H-pyrimido[1,2- b]pyridazin-4-one 16 4942-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 264-268 423.4(4-ethylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin- 4-one 39 4952-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 239-245 437.5[(3R)-4-ethyl-3-methylpiperazin-1-yl]-4H- pyrido[1,2-a]pyrimidin-4-one39 496 2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 234-245 437.5[(3S)-4-ethyl-3-methylpiperazin-1-yl]-4H- pyrido[1,2-a]pyrimidin-4-one39 497 2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 278-281 451.3[(3R)-3-methyl-4-(propan-2-yl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 39 4982-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 264-270 451.3[(3S)-3-methyl-4-(propan-2-yl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 58* 4992-(2-methyl-1,3-benzoxazol-6-yl)-7-(piperidin-4-yl)- 126-128 362.24H-pyrimido[1,2-b]pyridazin-4-one 25 5002-(2-methyl-1,3-benzoxazol-6-yl)-7-(1- 272-275 376.4methylpiperidin-4-yl)-4H-pyrimido[1,2-b]pyridazin- 4-one 25 5017-(1-ethylpiperidin-4-yl)-2-(2-methyl-1,3- 284-286 390.4benzoxazol-6-yl)-4H-pyrimido[1,2-b]pyridazin-4- one 59* 5022-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7- ND 376.4(piperidin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one 25 5032-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1- 257-259 390.3methylpiperidin-4-yl)-4H-pyrazino[1,2-a]pyrimidin- 4-one 25 5042-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1- ND 404.3ethylpiperidin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4- one 57 5052-(1-methyl-1H-indazol-5-yl)-7-(1,2,3,6- 228-230 359.2tetrahydropyridin-4-yl)-4H-pyrazino[1,2- a]pyrimidin-4-one 23 5062-(1-methyl-1H-indazol-5-yl)-7-(1-methyl-1,2,3,6- 234-236 373.3tetrahydropyridin-4-yl)-4H-pyrazino[1,2- a]pyrimidin-4-one 23 5077-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(1- ND 387.4methyl-1H-indazol-5-yl)-4H-pyrazino[1,2- a]pyrimidin-4-one  2 5082-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4- 241-252 418.5ethylpiperazin-1-yl)-9-methyl-4H-pyrido[1,2- a]pyrimidin-4-one  2 5092-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9- 213-222 404.5methyl-7-[(3R)-3-methylpiperazin-1-yl]-4H- pyrido[1,2-a]pyrimidin-4-one 2 510 7-[(3R)-3,4-dimethylpiperazin-1-yl]-2-(4,6- 244-253 418.4dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one  2 5112-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7- 240-245 432.5[(3R)-4-ethyl-3-methylpiperazin-1-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one 60* 5122-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7- ND 376.4(piperidin-4-yl)-4H-pyrimido[1,2-b]pyridazin-4-one 25 5132-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1- 265-267 390.3methylpiperidin-4-yl)-4H-pyrimido[1,2-b]pyridazin- 4-one 25 5142-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1- 283-285 404.4ethylpiperidin-4-yl)-4H-pyrimido[1,2-b]pyridazin-4- one  2 5152-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7- 198-200 416.3(octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 24 5162-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 287-293 394.2(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 25 5172-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 292-296 408.3(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin- 4-one 25 5182-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 240-246 422.3(1-ethylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4- one 25 5192-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 279-285 436.5[1-(propan-2-yl)piperidin-4-yl]-4H-pyrido[1,2- a]pyrimidin-4-one  2 5202-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9- ND 418.3methyl-7-(4-methyl-1,4-diazepan-1-yl)-4H- pyrido[1,2-a]pyrimidin-4-one58 521 2-(2-methyl-2H-indazol-5-yl)-7-(piperidin-4-yl)-4H- ND 361.4pyrimido[1,2-b]pyridazin-4-one 25 5222-(2-methyl-2H-indazol-5-yl)-7-(1-methylpiperidin- 260-262 375.24-yl)-4H-pyrimido[1,2-b]pyridazin-4-one 25 5237-(1-ethylpiperidin-4-yl)-2-(2-methyl-2H-indazol-5- 253-255 389.3yl)-4H-pyrimido[1,2-b]pyridazin-4-one 25 5242-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 289-291 409.3(1-methylpiperidin-4-yl)-4H-pyrimido[1,2- b]pyridazin-4-one 25 5252-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 284-286 423.2(1-ethylpiperidin-4-yl)-4H-pyrimido[1,2- b]pyridazin-4-one 25 5262-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 255-257 439.3[1-(2-hydroxyethyl)piperidin-4-yl]-4H-pyrimido[1,2- b]pyridazin-4-one 50527 2-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-[(3R,5S)- 260-262 404.33,5-dimethylpiperazin-1-yl]-4H-pyrido[1,2- a]pyrimidin-4-one 50 5287-[4-(dimethylamino)piperidin-1-yl]-2-(5,7- 200-202 418.3dimethylfuro[2,3-c]pyridin-2-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 50 5292-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-[4-(2- 256-258 420.3hydroxyethyl)piperazin-1-yl]-4H-pyrido[1,2- a]pyrimidin-4-one 25 5302-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(2- 228-230 419.3hydroxyethyl)piperidin-4-yl]-4H-pyrido[1,2- a]pyrimidin-4-one  9 5312-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(2- 246-248 420.4hydroxyethyl)piperazin-1-yl]-4H-pyrido[1,2- a]pyrimidin-4-one 39 5322-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7- 238-240 434.3[(3R)-4-(2-hydroxyethyl)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 43 5332-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 179-183 467.3[(3S)-4-(2-methoxyethyl)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 43 5342-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 201-205 497.3{(3S)-4-[2-(2-hydroxyethoxy)ethyl]-3-methylpiperazin-1-yl}-4H-pyrido[1,2-a]pyrimidin-4- one 39 5352-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 253-257 449.3[(3S)-4-cyclopropyl-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 39 5362-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 228-232 463.3[(3S)-4-cyclobutyl-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 43 5372-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 228-234 453.3[(3S)-4-(2-hydroxyethyl)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 43 5382-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 215-219 451.3[(3S)-4-(2-methoxyethyl)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 43 5392-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 270-274 437.3[(3S)-4-(2-hydroxyethyl)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 43 5402-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 175-181 481.3{(3S)-4-[2-(2-hydroxyethoxy)ethyl]-3-methylpiperazin-1-yl}-4H-pyrido[1,2-a]pyrimidin-4- one 39 5412-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 191-194 435.3[(3S)-3-methyl-4-(propan-2-yl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 39 5427-[(3S)-4-cyclopropyl-3-methylpiperazin-1-yl]-2-(8- 242-246 433.4fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 39 5437-[(3S)-4-cyclobutyl-3-methylpiperazin-1-yl]-2-(8- 264-267 447.3fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one  2 5447-(3,3-dimethylpiperazin-1-yl)-2-(4,6- ND 418.3dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one 14 5452-(1-methyl-1H-indazol-5-yl)-7-[(3R)-3- 190-192 375.3methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4- one  9 5462-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7- 230-233 390.5(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one  9 5472-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7- 250-252 404.5(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin- 4-one  9 5482-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7- 250-252 418.5(4-ethylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin- 4-one  9 5492-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7- 240-242 434.5[4-(2-hydroxyethyl)piperazin-1-yl]-4H-pyrido[1,2- a]pyrimidin-4-one  9550 7-[4-(dimethylamino)piperidin-1-yl]-2-(4-ethyl-6- 258-260 432.5methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2- a]pyrimidin-4-one  9551 7-[4-(diethylamino)piperidin-1-yl]-2-(4-ethyl-6- 232-235 460.6methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 14552 7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(1-methyl- 240-242 389.51H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 14 5532-(1-methyl-1H-indazol-5-yl)-7-[(3S)-3- 206-208 375.4methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4- one 25 5542-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-[1- 218-220 402.4(propan-2-yl)piperidin-4-yl]-4H-pyrido[1,2- a]pyrimidin-4-one 16 5552-(2-methylimidazo[1,2-a]pyridin-7-yl)-7-(piperazin- 272-277 361.31-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 24 5562-(2-methylimidazo[1,2-a]pyridin-7-yl)-7-(piperidin- 257-260 360.34-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 39 5572-(2-methylimidazo[1,2-a]pyridin-7-yl)-7-(4- 285-288 375.3methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4- one 39 5587-(4-ethylpiperazin-1-yl)-2-(2-methylimidazo[1,2- 219-222 389.3a]pyridin-7-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 25 5592-(2-methylimidazo[1,2-a]pyridin-7-yl)-7-(1- 255-260 374.3methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4- one 25 5607-(1-ethylpiperidin-4-yl)-2-(2-methylimidazo[1,2- 229-233 388.4a]pyridin-7-yl)-4H-pyrido[1,2-a]pyrimidin-4-one  2 5612-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9- 210-219 404.4methyl-7-[(3S)-3-methylpiperazin-1-yl]-4H- pyrido[1,2-a]pyrimidin-4-one 2 562 7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(4,6- 273-283 418.4dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one  2 5637-[(3S)-3,4-dimethylpiperazin-1-yl]-2-(4,6- 244-253 418.4dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one  2 5642-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9- 297-310 432.4methyl-7-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 23 5652-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-[1- 230-232 400.5(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 58 5662-(2-methyl-2H-indazol-5-yl)-7-(piperidin-4-yl)-4H- 235-237 361.3pyrazino[1,2-a]pyrimidin-4-one 25 5672-(2-methyl-2H-indazol-5-yl)-7-(1-methylpiperidin- 275-277 375.34-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one 25 5687-(1-ethylpiperidin-4-yl)-2-(2-methyl-2H-indazol-5- 198-200 389.3yl)-4H-pyrazino[1,2-a]pyrimidin-4-one 25 5697-[1-(2-hydroxyethyl)piperidin-4-yl]-2-(2-methyl- 230-232 405.32H-indazol-5-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one  9 5707-{4-[(dimethylamino)methyl]piperidin-1-yl}-2- 206-208 432.3(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one  9 5712-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4- 177-180 458.5(pyrrolidin-1-ylmethyl)piperidin-1-yl]-4H- pyrido[1,2-a]pyrimidin-4-one 9 572 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4- 192-195 472.6(piperidin-1-ylmethyl)piperidin-1-yl]-4H-pyrido[1,2- a]pyrimidin-4-one 9 573 2-(3,4-dimethoxyphenyl)-7-{4- 182-184 423.3[(dimethylamino)methyl]piperidin-1-yl}-4H- pyrido[1,2-a]pyrimidin-4-one 9 574 2-(3,4-dimethoxyphenyl)-7-[4-(pyrrolidin-1- 194-196 449.5ylmethyl)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin- 4-one  9 5752-(3,4-dimethoxyphenyl)-7-[4-(piperidin-1- 184-186 463.5ylmethyl)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin- 4-one 25 5767-[1-(2-hydroxyethyl)piperidin-4-yl]-2-(2- 200-202 404.4methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 23577 7-[1-(2-hydroxy ethyl)-1,2,3,6-tetrahydropyridin-4- 248-250 402.2yl]-2-(2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 25 5782-(2-methyl-2H-indazol-5-yl)-7-(1-methylpiperidin- 256-258 374.34-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 25 5792-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1- 277-280 375.3methylpiperidin-4-yl)-4H-pyrazino[1,2-a]pyrimidin- 4-one 25 5807-(1-ethylpiperidin-4-yl)-2-(2-methylimidazo[1,2- 255-258 389.3a]pyridin-6-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one 25 5817-[1-(2-hydroxyethyl)piperidin-4-yl]-2-(2- 250-252 405.3methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrazino[1,2- a]pyrimidin-4-one 53582 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-{4- 250-259 462.4[(2-hydroxyethyl)(methyl)amino]piperidin-1-yl}-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one 53 5832-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9- 231-241 446.4methyl-7-[4-(propylamino)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one  2 5847-(4-amino-4-methylpiperidin-1-yl)-2-(4,6- 200-203 404.5dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H- pyrido[1,2-a]pyrimidin-4-one 58585 2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperidin- ND 361.34-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one 61* 5862-(2-methyl-2H-indazol-5-yl)-7-(piperazin-1-yl)-4H- 160-162 362.3pyrazino[1,2-a]pyrimidin-4-one 58 5872-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- ND 395.3(piperidin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one 58 5882-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7- ND 375.4(piperidin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one 39 5892-(2-methyl-2H-indazol-5-yl)-7-(4-methylpiperazin- ND 376.41-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one 39 5907-(4-ethylpiperazin-1-yl)-2-(2-methyl-2H-indazol-5- 214-216 390.4yl)-4H-pyrazino[1,2-a]pyrimidin-4-one 39 5917-[4-(2-hydroxyethyl)piperazin-1-yl]-2-(2-methyl- 200-202 406.42H-indazol-5-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one 25 5922-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(1- 249-251 389.3methylpiperidin-4-yl)-4H-pyrazino[1,2-a]pyrimidin- 4-one 25 5932-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(1- 242-244 403.4ethylpiperidin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4- one 25 5942-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-[1-(2- 242-244 419.4hydroxyethyl)piperidin-4-yl]-4H-pyrazino[1,2- a]pyrimidin-4-one 25 5952-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 243-245 437.3[1-(propan-2-yl)piperidin-4-yl]-4H-pyrazino[1,2- a]pyrimidin-4-one 53596 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4- 228-236 432.4(ethylamino)piperidin-1-yl]-9-methyl-4H-pyrido[1,2- a]pyrimidin-4-one 53597 7-{4-[bis(2-hydroxyethyl)amino]piperidin-1-yl}-2- 218-227 492.4(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one 25 5987-[1-(2-hydroxyethyl)piperidin-4-yl]-2-(2-methyl- 205-207 406.31,3-benzoxazol-6-yl)-4H-pyrimido[1,2-b]pyridazin- 4-one 25 5992-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 266-268 439.3[1-(2-hydroxyethyl)piperidin-4-yl]-4H-pyrazino[1,2- a]pyrimidin-4-one 25600 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1- 150-152 431.3(oxetan-3-yl)piperidin-4-yl]-4H-pyrido[1,2- a]pyrimidin-4-one 50 6012-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-(4- 202-204 404.3ethylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4- one 39 6022-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1- 210-212 430.3methyloctahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 51* 6032-(1-methyl-1H-indazol-5-yl)-7-(piperidin-4-yl)-4H- 268-270 360.4pyrido[1,2-a]pyrimidin-4-one 25 6047-(1-ethylpiperidin-4-yl)-2-(1-methyl-1H-indazol-5- 184-186 388.5yl)-4H-pyrido[1,2-a]pyrimidin-4-one 25 6057-[1-(2-hydroxyethyl)piperidin-4-yl]-2-(1-methyl- 204-206 404.51H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 24 6062-(2-methyl-2H-indazol-5-yl)-7-(piperidin-4-yl)-4H- 194-196 360.4pyrido[1,2-a]pyrimidin-4-one 24 6072-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7- 282-284 374.3(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 25 6082-(2-methyl-2H-indazol-5-yl)-7-[1-(propan-2- ND 402.5yl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 53 6092-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-{4- 221-232 448.4[(2-hydroxyethyl)amino]piperidin-1-yl}-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one 53 6102-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9- 218-227 418.4methyl-7-[4-(methylamino)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 53 6112-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9- 215-225 446.4methyl-7-[4-(propan-2-ylamino)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 25 6127-(1-ethylpiperidin-4-yl)-2-(2-methyl-2H-indazol-5- 202-204 388.5yl)-4H-pyrido[1,2-a]pyrimidin-4-one 25 6137-[1-(2-hydroxyethyl)piperidin-4-yl]-2-(2-methyl- 170-172 404.52H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 25 6142-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(1- 200-202 388.5methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4- one 25 6152-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(1- 202-204 402.5ethylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4- one 25 6162-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-[1- 242-244 416.5(propan-2-yl)piperidin-4-yl]-4H-pyrido[1,2- a]pyrimidin-4-one 25 6172-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-[1-(2- ND 418.5hydroxyethyl)piperidin-4-yl]-4H-pyrido[1,2- a]pyrimidin-4-one  9 6182-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7- 243-245 432.5(4-propylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin- 4-one  9 6192-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7- 255-258 432.5[4-(propan-2-yl)piperazin-1-yl]-4H-pyrido[1,2- a]pyrimidin-4-one  9 6207-(4-cyclopropylpiperazin-1-yl)-2-(4-ethyl-6- 258-260 430.5methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 39621 7-(4-cyclobutylpiperazin-1-yl)-2-(4-ethyl-6- 275-278 444.5methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 39622 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7- 205-208 446.5[4-(oxetan-3-yl)piperazin-1-yl]-4H-pyrido[1,2- a]pyrimidin-4-one 39 6232-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1- 176-178 444.5ethyloctahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 39 6242-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(2- 184-187 460.5hydroxyethyl)octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 40* 6252-(4-methoxy-6-methylpyrazolo[1,5-a]pyrazin-2-yl)- 242-244 406.57-(4-methylpiperazin-1-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 40* 6262-(4-hydroxy-6-methylpyrazolo[1,5-a]pyrazin-2-yl)- 280-283 392.47-(4-methylpiperazin-1-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 25 6272-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-[1- 229-231 403.3(propan-2-yl)piperidin-4-yl]-4H-pyrazino[1,2- a]pyrimidin-4-one 25 6287-(1-cyclobutylpiperidin-4-yl)-2-(2- 249-251 415.2methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrazino[1,2- a]pyrimidin-4-one 39*629 7-[(3R)-3,4-dimethylpiperazin-1-yl]-2-(4-ethyl-6- 257-259 418.5methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 39630 7-[(3R)-4-ethyl-3-methylpiperazin-1-yl]-2-(4-ethyl- 256-258 432.56-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H- pyrido[1,2-a]pyrimidin-4-one 39631 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7- 243-245 446.5[(3R)-3-methyl-4-propylpiperazin-1-yl]-4H- pyrido[1,2-a]pyrimidin-4-one39 632 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7- 238-241 448.5[(3R)-4-(2-hydroxyethyl)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one  9 6337-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(4-ethyl-6- 258-260 418.4methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2- a]pyrimidin-4-one  9634 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7- 229-232 458.6[4-(pyrrolidin-1-yl)piperidin-1-yl]-4H-pyrido[1,2- a]pyrimidin-4-one  9635 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7- 202-204 404.4[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2- a]pyrimidin-4-one  9 6362-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7- 175-180 418.4(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 16 6372-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 264-271 389.4(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 16 6382-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 230-234 403.4[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2- a]pyrimidin-4-one 16 6392-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 232-236 403.4[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2- a]pyrimidin-4-one 25 6402-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1- 196-198 417.5(propan-2-yl)piperidin-4-yl]-4H-pyrido[1,2- a]pyrimidin-4-one 25 6417-(1-cyclopropylpiperidin-4-yl)-2-(4,6- 180-183 415.5dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H- pyrido[1,2-a]pyrimidin-4-one 25642 7-(1-cyclobutylpiperidin-4-yl)-2-(4,6- 189-191 429.5dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H- pyrido[1,2-a]pyrimidin-4-one 39643 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7- 242-244 446.5[(3R)-3-methyl-4-(propan-2-yl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 39 6447-[(3R)-4-cyclopropyl-3-methylpiperazin-1-yl]-2-(4- 244-247 444.5ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 39 6457-[(3R)-4-cyclobutyl-3-methylpiperazin-1-yl]-2-(4- 261-264 458.6ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 39 6462-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7- 216-219 460.5[(3R)-3-methyl-4-(oxetan-3-yl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 39 6472-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[4- 248-253 433.3(2-hydroxyethyl)piperazin-1-yl]-4H-pyrido[1,2- a]pyrimidin-4-one 39 6487-(4-cyclobutylpiperazin-1-yl)-2-(8-ethyl-2- 274-279 443.5methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 39649 2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 217-220 447.4[(3R)-4-(2-hydroxyethyl)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 39 6507-[(3R)-4-cyclobutyl-3-methylpiperazin-1-yl]-2-(8- 209-212 457.4ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 39 6512-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 220-223 447.4[(3S)-4-(2-hydroxyethyl)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 39 6527-[(3S)-4-cyclobutyl-3-methylpiperazin-1-yl]-2-(8- ND 457.5ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 59 6532-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7- ND 390.4(piperidin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one 25 6542-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7- 261-263 404.5(1-methylpiperidin-4-yl)-4H-pyrazino[1,2- a]pyrimidin-4-one 25 6552-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7- 273-275 418.3(1-ethylpiperidin-4-yl)-4H-pyrazino[1,2-a]pyrimidin- 4-one 24 6562-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7- 236-238 389.4(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 25 6572-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7- 190-192 403.5(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin- 4-one 25 6582-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7- 194-196 417.5(1-ethylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4- one 25 6592-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7- 207-209 433.5[1-(2-hydroxyethyl)piperidin-4-yl]-4H-pyrido[1,2- a]pyrimidin-4-one 25660 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7- 203-204 431.5(1-propylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin- 4-one  9 6612-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7- 185-188 404.5[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2- a]pyrimidin-4-one 43* 6622-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(2- 197-199 421.5fluoroethyl)piperidin-4-yl]-4H-pyrido[1,2- a]pyrimidin-4-one 43 6632-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(3- 186-188 435.5fluoropropyl)piperidin-4-yl]-4H-pyrido[1,2- a]pyrimidin-4-one 43 6642-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7- 245-247 436.5[4-(2-fluoroethyl)piperazin-1-yl]-4H-pyrido[1,2- a]pyrimidin-4-one 43665 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7- 240-242 450.6[4-(3-fluoropropyl)piperazin-1-yl]-4H-pyrido[1,2- a]pyrimidin-4-one 43666 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7- 255-257 450.6[(3R)-4-(2-fluoroethyl)-3-methylpiperazin-l-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 43 6672-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7- 244-246 464.6[(3R)-4-(3-fluoropropyl)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 43 6682-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7- 206-208 435.6[1-(2-fluoroethyl)piperidin-4-yl]-4H-pyrido[1,2- a]pyrimidin-4-one 43669 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7- 216-218 449.6[1-(3-fluoropropyl)piperidin-4-yl]-4H-pyrido[1,2- a]pyrimidin-4-one 43670 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7- ND 492.4{(3R)-4-[2-(2-hydroxyethoxy)ethyl]-3-methylpiperazin-1-yl}-9-methyl-4H-pyrido[1,2- a]pyrimidin-4-one 24 6712-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9- 247-255 389.3methyl-7-(piperidin-4-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 25 6722-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9- 237-248 403.4methyl-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 39673 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7- 273-281 448.4[(3R)-4-(2-hydroxyethyl)-3-methylpiperazin-1-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one 48* 6742-[8-(hydroxymethyl)-2-methylimidazo[1,2- >320 391.3a]pyridin-6-yl]-7-(piperazin-1-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 16675 7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(8-ethyl-2- ND 417.4methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 16676 2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(4- ND 417.3methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 39 6772-[8-(hydroxymethyl)-2-methylimidazo[1,2- 262-266 405.3a]pyridin-6-yl]-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 39 678 7-(4-ethylpiperazin-1-yl)-2-[8-(hydroxymethyl)-2- 258-262 419.3methylimidazo[1,2-a]pyridin-6-yl]-4H-pyrido[1,2- a]pyrimidin-4-one 25679 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7- 228-230 431.5[1-(propan-2-yl)piperidin-4-yl]-4H-pyrido[1,2- a]pyrimidin-4-one 25 6807-(1-cyclopropylpiperidin-4-yl)-2-(4-ethyl-6- 196-199 429.5methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 25681 7-(1-cyclobutylpiperidin-4-yl)-2-(4-ethyl-6- 227-229 443.5methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 25682 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7- 190-192 445.5[1-(oxetan-3-yl)piperidin-4-yl]-4H-pyrido[1,2- a]pyrimidin-4-one  9 6832-(4-cyclopropyl-6-methylpyrazolo[1,5-a]pyrazin-2- 226-229 402.4yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4- one  9 6842-(4-cyclopropyl-6-methylpyrazolo[1,5-a]pyrazin-2- 238-240 416.5yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2- a]pyrimidin-4-one  9 6852-(4-cyclopropyl-6-methylpyrazolo[1,5-a]pyrazin-2- 236-238 430.5yl)-7-(4-ethylpiperazin-1-yl)-4H-pyrido[1,2- a]pyrimidin-4-one  9 6862-(4-cyclopropyl-6-methylpyrazolo[1,5-a]pyrazin-2- 239-241 446.5yl)-7-[4-(2-hydroxyethyl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 25 6872-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1- 185-187 417.4propylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4- one 41* 6882-[4-(dimethylamino)-6-methylpyrazolo[1,5- 245-248 405.4a]pyrazin-2-yl]-7-(piperazin-1-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 14689 2-(2-methyl-1H-benzimidazol-6-yl)-7-(4- 292-294 375.3methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4- one 39 6907-(4-ethylpiperazin-1-yl)-2-(2-methyl-1H- 283-285 389.3benzimidazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 58 6912-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7- 215-217 375.4(piperidin-4-yl)-4H-pyrimido[1,2-b]pyridazin-4-one 58 6922-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperidin- 249-251 361.34-yl)-4H-pyrimido[1,2-b]pyridazin-4-one 25 6937-[1-(2,2-dimethyl-1,3-dioxan-5-yl)piperidin-4-yl]- 236-238 503.52-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 42* 6947-[1-(1,3-dihydroxypropan-2-yl)piperidin-4-yl]-2-(4- 228-230 463.6ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 62* 6957-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(1,3- 254-256 403.4dimethylpyrrolo[1,2-a]pyrazin-7-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 24696 2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 221-224 388.3(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 25 6972-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1- 214-218 402.4methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4- one 25 6982-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1- 196-200 416.5ethylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4- one 25 6992-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[1- 244-247 432.4(2-hydroxyethyl)piperidin-4-yl]-4H-pyrido[1,2- a]pyrimidin-4-one 39 7007-[(3R)-3,4-dimethylpiperazin-1-yl]-2-(8-ethyl-2- 217-220 417.4methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 39701 2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 179-182 431.4[(3R)-4-ethyl-3-methylpiperazin-1-yl]-4H- pyrido[1,2-a]pyrimidin-4-one25 702 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1- 231-240 417.4ethylpiperidin-4-yl)-9-methyl-4H-pyrido[1,2- a]pyrimidin-4-one 25 7032-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(2- 224-233 433.3hydroxyethyl)piperidin-4-yl]-9-methyl-4H- pyrido[1,2-a]pyrimidin-4-one25 704 7-(1-cyclobutylpiperidin-4-yl)-2-(4,6- 228-237 443.5dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one 25 7059-methyl-2-(2-methyl-2H-indazol-5-yl)-7-(1- 222-227 388.3methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4- one  2 7067-[4-(dimethylamino)-4-methylpiperidin-1-yl]-2- 237-239 432.4(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one  2 7072-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4- 187-189 432.4(ethylamino)-4-methylpiperidin-1-yl]-4H-pyrido[1,2- a]pyrimidin-4-one  2708 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4- 181-183 446.4methyl-4-(propylamino)piperidin-1-yl]-4H- pyrido[1,2-a]pyrimidin-4-one 2 709 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-{4- 196-198 448.4[(2-hydroxyethyl)amino]-4-methylpiperidin-1-yl}-4H-pyrido[1,2-a]pyrimidin-4-one 25 7107-(1-cyclobutylpiperidin-4-yl)-9-methyl-2-(2- 232-235 428.4methyl-2H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin- 4-one 25 7117-[1-(2-hydroxyethyl)piperidin-4-yl]-9-methyl-2-(2- 216-222 418.4methyl-2H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin- 4-one 25 7122-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9- 216-223 431.4methyl-7-(1-propylpiperidin-4-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 62713 2-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-[(3R)- ND 389.33-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin- 4-one 47* 7142-(8-cyclopropyl-2-methylimidazo[1,2-a]pyridin-6- 274-277 401.4yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4- one 47 7152-(8-cyclopropyl-2-methylimidazo[1,2-a]pyridin-6- 246-250 415.4yl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2- a]pyrimidin-4-one 47716 2-(8-cyclopropyl-2-methylimidazo[1,2-a]pyridin-6- 246-250 415.4yl)-7-[(3 S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2- a]pyrimidin-4-one 47717 2-(8-cyclopropyl-2-methylimidazo[1,2-a]pyridin-6- 205-209 429.5yl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 25 7187-(1-cyclopropylpiperidin-4-yl)-9-methyl-2-(2- 226-231 414.4methyl-2H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin- 4-one 25 7197-(1-ethylpiperidin-4-yl)-9-methyl-2-(2-methyl-2H- 237-241 402.5indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one  2 7202-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9- 254-264 390.4methyl-7-(piperazin-1-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 24 7219-methyl-2-(2-methyl-2H-indazol-5-yl)-7-(piperidin- 211 (S), 374.34-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 223-227 27 7222-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(1- 249-252 405.4methylpiperidin-4-yl)oxy]-4H-pyrido[1,2- a]pyrimidin-4-one  9 7232-(6-methyl-4-propylpyrazolo[1,5-a]pyrazin-2-yl)-7- 250-252 404.4(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one  9 7247-(4-methylpiperazin-1-yl)-2-(6-methyl-4- 246-248 418.4propylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2- a]pyrimidin-4-one  9725 7-(4-ethylpiperazin-1-yl)-2-(6-methyl-4- 231-233 432.5propylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2- a]pyrimidin-4-one  9726 7-[4-(2-hydroxyethyl)piperazin-1-yl]-2-(6-methyl-4- 225-227 448.4propylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2- a]pyrimidin-4-one  9727 7-[(3R)-3-methylpiperazin-1-yl]-2-(6-methyl-4- 195-197 418.4propylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2- a]pyrimidin-4-one  9728 7-[(3S)-3-methylpiperazin-1-yl]-2-(6-methyl-4- 195-197 418.4propylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2- a]pyrimidin-4-one  9729 7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(6-methyl- 249-251 432.54-propylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 39730 2-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-[(3R)- 249-251 431.33-methyl-4-(propan-2-yl)piperazin-1-yl]-4H- pyrido[1,2-a]pyrimidin-4-one63* 731 7-(4-amino-4-methylpiperidin-1-yl)-2-(1,3- 244-246 403.3dimethylpyrrolo[1,2-a]pyrazin-7-yl)-4H-pyrido[1,2- a]pyrimidin-4-one  2732 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3S)- 243-251 418.53-ethylpiperazin-1-yl]-9-methyl-4H-pyrido[1,2- a]pyrimidin-4-one 16 7332-[2-methyl-8-(trifluoromethyl)imidazo[1,2- 325-328 429.3a]pyridin-6-yl]-7-(piperazin-1-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 16734 7-[(3R)-3-methylpiperazin-1-yl]-2-[2-methyl-8- 303-306 443.2(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 16 7357-[(3S)-3-methylpiperazin-1-yl]-2-[2-methyl-8- >320 443.2(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 16 7367-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-[2-methyl- 293-296 457.38-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]-4H-pyrido[1,2-a]pyrimidin-4-one  2 7377-(4-amino-4-methylpiperidin-1-yl)-2-(4-ethyl-6- 216-218 418.5methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 14738 2-(2,7-dimethyl-2H-indazol-5-yl)-7-(piperazin-1-yl)- 194-196 375.44H-pyrido[1,2-a]pyrimidin-4-one 24 7392-(2,7-dimethyl-2H-indazol-5-yl)-7-(piperidin-4-yl)- 228-230 374.44H-pyrido[1,2-a]pyrimidin-4-one 52 740 7-(3-aminoprop-1-yn-1-yl)-2-(4,6-242-244 345.4 dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 14 7412-(2,7-dimethyl-2H-indazol-5-yl)-7-[(3R)-3- 170-172 389.4methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4- one 52 7427-(3-aminopropyl)-2-(4,6-dimethylpyrazolo[1,5- ND 349.3a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 64* 7432-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7- 189-191 372.3(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 38 7442-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7- 218-221 429.5(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 38 7452-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7- 255-258 443.5(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 45 7462-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7- 239-242 402.4[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one  2 7472-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7- 246-249 416.4[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 62 7487-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(1-ethyl-3- 238-241 417.4methylpyrrolo[1,2-a]pyrazin-7-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 62749 7-(1,4-diazepan-1-yl)-2-(1-ethyl-3- 200-202 403.4methylpyrrolo[1,2-a]pyrazin-7-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 14750 2-(2,7-dimethyl-2H-indazol-5-yl)-7-[(3S)-3- 308-310 389.4methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4- one 39 7512-(2,7-dimethyl-2H-indazol-5-yl)-7-[(3S)-3,4- 202-204 403.4dimethylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin- 4-one 25 7522-(2,7-dimethyl-2H-indazol-5-yl)-7-(1- 208-210 388.3methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4- one 25 7532-(2,7-dimethyl-2H-indazol-5-yl)-7-(1- 162-164 402.4ethylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4- one  2 7549-methyl-2-(2-methyl-2H-indazol-5-yl)-7-(piperazin- 233-243 375.31-yl)-4H-pyrido[1,2-a]pyrimidin-4-one  2 7559-methyl-2-(2-methyl-2H-indazol-5-yl)-7-[(3R)-3- ND 389.4methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4- one  2 7569-methyl-2-(2-methyl-2H-indazol-5-yl)-7-[(3S)-3- ND 389.3methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4- one  2 7577-[3-(dimethylamino)azetidin-1-yl]-2-(4,6- 226-228 390.4dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H- pyrido[1,2-a]pyrimidin-4-one  2758 7-[3-(diethylamino)azetidin-1-yl]-2-(4,6- 231-233 418.5dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H- pyrido[1,2-a]pyrimidin-4-one  2759 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[3- 235-237 416.4(pyrrolidin-1-yl)azetidin-1-yl]-4H-pyrido[1,2- a]pyrimidin-4-one  9 7607-(1,4-diazepan-1-yl)-2-(4-ethyl-6- 212-214 404.4methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 45761 7-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)- 212-214 430.4yl]-2-(6-methyl-4-propylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 38 7622-(6-methyl-4-propylpyrazolo[1,5-a]pyrazin-2-yl)-7- 257-260 401.4(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 38 7632-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7- 287-289 387.4(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 45*764 7-[(3S)-3-(aminomethyl)pyrrolidin-1-yl]-2-(4,6- 244-246 390.4dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H- pyrido[1,2-a]pyrimidin-4-one  2765 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[3- 220-223 430.5(piperidin-1-yl)azetidin-1-yl]-4H-pyrido[1,2- a]pyrimidin-4-one 24 7662-(6-methyl-4-propylpyrazolo[1,5-a]pyrazin-2-yl)-7- 228-230 403.4(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one  2 7677-(2,7-diazaspiro[4.4]non-2-yl)-2-(4,6- 208-210 416.4dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H- pyrido[1,2-a]pyrimidin-4-one 14768 2-(2,7-dimethyl-2H-indazol-5-yl)-7-(4- 216-218 389.5methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4- one 52* 7697-[3-(dimethylamino)propyl]-2-(4,6- 136-138 377.3dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H- pyrido[1,2-a]pyrimidin-4-one 39770 7-{(3S)-3-[(dimethylamino)methyl]pyrrolidin-1-yl}- 239-241 418.42-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 24 7712-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-9- 241-249 403.4methyl-7-(piperidin-4-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 24 7729-methyl-2-(1-methyl-1H-indazol-5-yl)-7-(piperidin- 212-217 374.34-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 22 7732-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-9- 265 (D) 401.3methyl-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 25 7742-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-9- 220-227 417.3methyl-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 51775 2-(1,7-dimethyl-1H-indazol-5-yl)-7-(piperidin-4-yl)- 220-222 374.24H-pyrido[1,2-a]pyrimidin-4-one 14 7762-(1,7-dimethyl-1H-indazol-5-yl)-7-(piperazin-1-yl)- 160-163 375.34H-pyrido[1,2-a]pyrimidin-4-one 14 7772-(1,7-dimethyl-1H-indazol-5-yl)-7-[(3S)-3- 248-250 389.3methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4- one 39 7787-{(3S)-3-[(diethylamino)methyl]pyrrolidin-1-yl}-2- 194-196 446.4(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 39 7792-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7- ND 418.4{(3S)-3-[(ethylamino)methyl]pyrrolidin-1-yl}-4H-pyrido[1,2-a]pyrimidin-4-one  2 7807-{3-[(dimethylamino)methyl]azetidin-1-yl}-2-(4,6- 228-230 404.4dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H- pyrido[1,2-a]pyrimidin-4-one  2781 7-{3-[(diethylamino)methyl]azetidin-1-yl}-2-(4,6- 205-207 432.4dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H- pyrido[1,2-a]pyrimidin-4-one 62782 2-(1-ethyl-3-methylpyrrolo[1,2-a]pyrazin-7-yl)-7- 220-222 429.3[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one  2 7832-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-9- 223-233 418.4methyl-7-[(3R)-3-methylpiperazin-1-yl]-4H- pyrido[1,2-a]pyrimidin-4-one25 784 9-methyl-2-(1-methyl-1H-indazol-5-yl)-7-(1- 255-263 388.3methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4- one 39 7857-[(3R)-3,4-dimethylpiperazin-1-yl]-2-(4-ethyl-6- 234-240 432.4methylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one 25 7867-(1-ethylpiperidin-4-yl)-9-methyl-2-(1-methyl-1H- 236-240 402.4indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one  2 7872-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-9- 227-236 418.4methyl-7-[(3S)-3-methylpiperazin-1-yl]-4H- pyrido[1,2-a]pyrimidin-4-one 2 788 7-[1-(2-hydroxyethyl)piperidin-4-yl]-9-methyl-2-(1- 225-228 418.4methyl-1H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin- 4-one  2 7897-[(3S)-3,4-dimethylpiperazin-1-yl]-2-(4-ethyl-6- 235-241 432.4methylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one 25 7902-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7- 201-208 431.4(1-ethylpiperidin-4-yl)-9-methyl-4H-pyrido[1,2- a]pyrimidin-4-one 22 7919-methyl-2-(2-methyl-2H-indazol-5-yl)-7-(1,2,3,6- >240 373.3tetrahydropyridin-4-yl)-4H-pyrazino[1,2- (D) a]pyrimidin-4-one 25 7927-(1-cyclobutylpiperidin-4-yl)-2-(4-ethyl-6- 231-237 457.3methylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one 25 7932-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7- 210-216 447.4[1-(2-hydroxyethyl)piperidin-4-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one 16 7942-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 231-235 429.3[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 16 7952-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7- 229-233 429.3[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 51 7969-methyl-2-(2-methyl-2H-indazol-5-yl)-7-(piperidin- 229-235 375.34-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one  2 7977-[(3R)-3-(aminomethyl)pyrrolidin-1-yl]-2-(4,6- 214-217 390.4dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H- pyrido[1,2-a]pyrimidin-4-one44* 798 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7- 228-231 401.3[(2S,6S)-2,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one  2 7997-{(3R)-3-[(dimethylamino)methyl]pyrrolidin-1-yl}- 229-231 418.42-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 24 8007-[(2S,6S)-2,6-dimethylpiperidin-4-yl]-2-(4,6- 248-250 403.3dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H- pyrido[1,2-a]pyrimidin-4-one 16801 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- ND 423.5[4-(2-hydroxyethyl)piperazin-1-yl]-4H-pyrido[1,2- a]pyrimidin-4-one 16802 2-(imidazo[1,2-a]pyridin-6-yl)-7-(4-methylpiperazin- ND 361.51-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 36 8032-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-7-[(8aS)- ND 420.6hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 65* 8047-(2,7-diazaspiro[3.5]non-7-yl)-2-(4,6- ND 416.2dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H- pyrido[1,2-a]pyrimidin-4-one 14805 7-(4-methylpiperazin-1-yl)-2-(2- ND 376.1methyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 16 8067-(4-methylpiperazin-1-yl)-2-[2-methyl-8- ND 443.6(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 16 8072-methyl-6-[7-(4-methylpiperazin-1-yl)-4-oxo-4H- ND 400.6pyrido[1,2-a]pyrimidin-2-yl]imidazo[1,2-a]pyridine- 8-carbonitrile 16808 2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(4- ND 389.5methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4- one 16 8097-(4,7-diazaspiro[2.5]oct-7-yl)-2-(2,8- ND 401.4dimethylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 25810 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- ND 392.4(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin- 4-one 66* 8112-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- ND 394.4(4-hydroxypiperidin-4-yl)-4H-pyrido[1,2- a]pyrimidin-4-one  9 8122-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7- ND 430.7[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one  9 8132-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7- ND 430.6[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one  9 8147-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-2-(4- ND 418.7ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one  9 8157-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-2-(4- ND 418.7ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 16 8162-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- ND 433.6[(8aS)-8a-methylhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one  9 8172-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7- ND 432.6(4-ethylpiperazin-1-yl)-9-methyl-4H-pyrido[1,2- a]pyrimidin-4-one  9 8182-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7- ND 444.6[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one 16 8192-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(4- ND 403.7ethylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4- one 16 8202-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-[(8aS)- ND 415.7hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one 16 8212-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(8a- ND 429.7methylhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-4H-pyrido[1,2-a]pyrimidin-4-one  9 8227-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-2-(4- ND 432.6ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one  9 8232-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7- ND 434.6{[2-(morpholin-4-yl)ethyl]amino}-4H-pyrido[1,2- a]pyrimidin-4-one  9 8247-{[2-(dimethylamino)ethyl]amino}-2-(4-ethyl-6- ND 392.6methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2- a]pyrimidin-4-one  9825 7-{[2-(dimethylamino)ethyl](methyl)amino}-2-(4- ND 406.6ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one  9 8262-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7- ND 392.6{methyl[2-(methylamino)ethyl]amino}-4H- pyrido[1,2-a]pyrimidin-4-one 16827 7-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-2-(2,8- ND 403.7dimethylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 16828 7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-2-(2,8- ND 403.7dimethylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 27829 7-[2-(dimethylamino)ethoxy]-2-(4-ethyl-6- ND 407.6methylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one 27 8307-[2-(dimethylamino)ethoxy]-2-(4-ethyl-6- ND 393.6methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2- a]pyrimidin-4-one 27831 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7- ND 419.5(piperidin-4-ylmethoxy)-4H-pyrido[1,2-a]pyrimidin- 4-one 27 8322-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7- ND 433.6[2-(piperidin-1-yl)ethoxy]-4H-pyrido[1,2- a]pyrimidin-4-one 27 8332-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7- ND 449.6[3-(morpholin-4-yl)propoxy]-4H-pyrido[1,2- a]pyrimidin-4-one 27 8347-[3-(dimethylamino)propoxy]-2-(4-ethyl-6- ND 407.6methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2- a]pyrimidin-4-one  9835 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7- ND 416.5[(3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one

or a salt, isotopologue, stereoisomer, racemate, enantiomer,diastereomer or tautomer thereof.

Table 2 further provides certain isolated compounds of a salt form of acompound of Formula (I) that may be prepared according to the proceduresof the indicated Example by using the appropriate reactants, reagentsand reaction conditions. The preparation of any free base, isotopologue,stereoisomer, racemate, enantiomer, diastereomer or tautomer from a saltform of a compound of Formula (I) is also contemplated and furtherincluded within the scope of the description herein. Where a free baseform of the compound was not isolated from the salt form, a person ofordinary skill in the art could be expected to perform the requiredreactions to prepare and isolate the free base form of the compound.

The term “Cpd” represents Compound number, the term “Ex” represents“Example Number” (wherein * indicates that the corresponding Example forthe Compound is provided above), the term “M.P.” represents “MeltingPoint (oC),” the term “MS” represents “Mass Spectroscopy Peak(s) m/z[M+H]⁺, [M+2+H]⁺, [M−H]⁻ or [M+2−H]⁻,” the term “D” represents“Decomposition/Decomposed,” the term “DR” represents “DecompositionRange,” the term “S” represents “Softens” and the term “ND” indicatesthat the value was “Not Determined.”

TABLE 2 Ex Cpd Name M.P. MS  1 712-(3,5-difluoro-4-hydroxyphenyl)-7-(piperazin-1-yl)-4H- 290 (D) 359.2pyrido[1,2-a]pyrimidin-4-one hydrochloride 33 2037-[4-(dimethylamino)piperidin-1-yl]-2-(3-fluoro-4- 188-192 396.2methoxyphenyl)-4H-quinolizin-4-one acetate  55* 3802-(2-methyl-1,3-benzothiazol-6-yl)-7-(piperidin-4-yl)-4H- 230-235 378.2pyrimido[1,2-b]pyridazin-4-one trifluoroacetate (1:1) 57 4132-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-(1,2,3,6- >300 373.3tetrahydropyridin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4- one hydrochloride(1:2)

or a free base, isotopologue, stereoisomer, racemate, enantiomer,diastereomer or tautomer thereof.

Biological Examples

To describe in more detail and assist in understanding the presentdescription, the following non-limiting biological examples are offeredto more fully illustrate the scope of the description and are not to beconstrued as specifically limiting the scope thereof. Such variations ofthe present description that may be now known or later developed, whichwould be within the purview of one skilled in the art to ascertain, areconsidered to fall within the scope of the present description and ashereinafter claimed. These examples illustrate the testing of certaincompounds described herein in vitro and/or in vivo and demonstrate theusefulness of the compounds for treating of SMA by enhancing theinclusion of exon 7 of SMN2 into mRNA transcribed from the SMN2 gene.Compounds of Formula (I) enhance inclusion of exon 7 of SMN2 into mRNAtranscribed from the SMN2 gene and increase levels of Smn proteinproduced from the SMN2 gene, and thus can be used to treat SMA in ahuman subject in need thereof.

Example 1

SMN2 Minigene Construct

Preparation of the Minigene Constructs

DNA corresponding to a region of the SMN2 gene starting from the 5′ endof exon 6 (ATAATTCCCCC) (SEQ ID NO. 14) and ending at nucleic acidresidue 23 of exon 8 (CAGCAC) (SEQ ID NO. 15) was amplified by PCR usingthe following primers:

Forward primer: (SEQ ID NO. 16) 5′-CGCGGATCCATAATTCCCCCACCACCTC-3′Reverse primer: (SEQ ID NO. 17) 5′-CGCGGATCCGTGCTGCTCTATGCCAGCA-3′

The 5′ end of each primer was designed to add a BamHI restrictionendonuclease recognition site at both the 5′ end of exon 6 (GGATCC) (SEQID NO. 18) and the 3′ end after the 23^(rd) nucleotide of exon 8. Usingthe BamHI restriction endonuclease recognition sites, the PCR fragmentwas cloned into a derivative of the original pcDNA 3.1/Hygro vectorwhich was modified as disclosed in United States Patent PublicationUS2005/0048549.

New UTRs were added to the modified vector using the HindIII site andthe BamHI restriction sites comprising a 5′DEG UTR:5′-TAGCTTCTTACCCGTACTCCACCGTTGGCAGCACGATCGCACGTCCCACGTGAACCATTGGTAAACCCTG-3′ (SEQ ID NO. 19) cloned into the modifiedpcDNA3.1/Hygro vector together with a start codon upstream of the BamHIrestriction site, and;

a 3′DEG UTR: 5′-ATCGAAAGTACAGGACTAGCCTTCCTAGCAACCGCGGGCTGGGAGTCTGAGACATCACTCAAGATATATGCTCGGTAACGTATGCTCTAGCCATCTAACTATTCCCTATGTCT TATAGGG-3′(SEQ ID NO. 20) cloned into the modified pcDNA3.1/Hygro vector using theNotI restriction endonuclease recognition site and the XhoI restrictionendonuclease recognition site with a stop codon immediately downstreamof the NotI restriction site. In addition, a firefly luciferase genelacking the start codon was cloned into the vector using the BamHI andNotI restriction sites.

The resulting minigene comprises, in 5′ to 3′ order: the 5′-DEG UTR, thestart codon, six additional nucleotides forming a BamHI restrictionsite, the nucleic acid residues of exon 6, the nucleic acid residues ofintron 6 of SMN2, the nucleic acid residues of exon 7 of SMN2, thenucleic acid residues of intron 7 of SMN2, and the first 23 nucleic acidresidues of exon 8 of SMN2, an additional six nucleotides forming aBamHI restriction site and the firefly luciferase gene lacking the startcodon.

A single adenine residue was inserted after nucleotide 48 of exon 7 ofSMN2 by site-directed mutagenesis. This minigene construct is referredto as SMN2-A.

SMN2 transcripts derived from minigenes containing exon 6 through 8 andthe intervening introns recapitulate the splicing of their endogenouspre-mRNA (Lorson et al, Proc. Natl. Acad. Sci. U.S.A., 1999, 96 (11),6307). An SMN2-alternative splicing reporter construct which containsexons 6 through 8 and the intervening introns followed by a luciferasereporter gene was generated. Salient features of this construct are thelack of the start codon in the luciferase gene, inactivation of thetermination codon (in the open reading frame that encodes the SMNprotein) of exon 7 by insertion of a nucleotide after nucleic acid 48 ofexon 7 and addition of a start codon (ATG) immediately upstream of exon6. A single adenine (SMN2-A) was inserted after nucleic residue 48 ofexon 7.

The SMN2 minigene was designed such that the luciferase reporter is inframe with the ATG start codon immediately upstream of exon 6 when exon7 is present in the mRNA and the luciferase reporter is out of framewith the ATG start codon immediately upstream of exon 6 if exon 7 ofSMN2 is removed during splicing of the pre-mRNA. In addition, in theabsence of exon 7, the open reading frame that starts from the ATG startcodon immediately upstream of exon 6 contains a stop codon in thefragment of exon 8 of SMN. Thus, in the presence of compounds thatincrease the inclusion of exon 7 of SMN2 into mRNA transcribed from theSMN2 gene, more transcripts containing exon 7 and more functionalreporter are produced. A schematic illustration of this description canbe found in FIG. 1.

The DNA sequence of the minigene from the SMN2-A construct SEQ ID NO. 21is provided in FIG. 2a . A picture of the minigene SMN2-A subsequencesis shown in FIG. 2 b.

Example 2

SMN2 Minigene mRNA Splicing RT-qPCR Assay in Cultured Cells

The reverse transcription-quantitative PCR-based (RT-qPCR) assay is usedto quantify the level of the full length SMN2 minigene mRNA containingSMN2 exon 7 in a HEK293H cell line stably transfected with said minigeneand treated with a test compound.

Materials

Material Source HEK293H cells ATCC Catalog No. CRL-1573 Cells-To-Ctlysis buffer Life Technologies, Inc. (formerly Applied Biosystems)Catalog No.: 4399002 DMEM Life Technologies, Inc. (formerly Invitrogen)Catalog No.: 11960-044 96-well flat- Becton Dickinson Catalog No.:353072 bottom plates RT-PCR Enzyme Mix Life Technologies, Inc. (formerlyApplied Biosystems) Part No.: 4388520 (also included in AgPath-ID KitCatalog No.: 4387391) RT-PCR buffer Life Technologies, Inc. (formerlyApplied Biosystems) Part No.: 4388519 (also included in AgPath-ID KitCatalog No.: 4387391) AgPath-ID One-Step RT- Life Technologies, Inc.(formerly Applied PCR Kit Biosystems) Catalog No.: 4387391 ThermocyclerLife Technologies, Inc. (formerly Applied Biosystems) 7900HT

Protocol.

HEK293H cells stably transfected with the SMN2-A minigene constructdescribed above (10,000 cells/well) are seeded in 200 μL of cell culturemedium (DMEM plus 10% FBS, with 200 μg/mL hygromycin) in 96-wellflat-bottom plates and the plate is immediately swirled to ensure properdispersal of cells, forming an even monolayer of cells. Cells areallowed to attach for at least 4-6 hours. Test compounds are seriallydiluted 3.16-fold in 100% DMSO to generate a 7-point concentrationcurve. A solution of test compound (1 μL, 200× in DMSO) is added to eachcell-containing well and the plate is incubated for 24 hours in a cellculture incubator (37° C., 5% CO₂, 100% relative humidity). 2 replicatesare prepared for each test compound concentration. The cells are thenlysed in Cells-To-Ct lysis buffer and the lysate is stored at −80° C.

Full length SMN2-A minigene and GAPDH mRNA are quantified using thefollowing primers and probes provided in Table 3. Primer SMN Forward A(SEQ ID NO. 1) hybridizes to a nucleotide sequence in exon 7 (nucleotide22 to nucleotide 40), primer SMN Reverse A (SEQ ID NO. 2) hybridizes toa nucleotide sequence in the coding sequence of Firefly luciferase, SMNProbe A (SEQ ID NO. 3) hybridizes to a nucleotide sequence in exon 7(nucleotide 50 to nucleotide 54) and exon 8 (nucleotide 1 to nucleotide21). The combination of these three oligonucleotides detects only SMN1or SMN2 minigenes (RT-qPCR) and will not detect endogenous SMN1 or SMN2genes.

TABLE 3 Primers/Probes Sequence Source SMN ForwardSEQ ID NO. 1: GAAGGAAGGTGCTCACATT PTC¹ Primer A SMN ReverseSEQ ID NO. 2: TCTTTATGTTTTTGGCGTCTTC PTC¹ Primer A SMN ForwardSEQ ID NO. 3: 6FAM- PTC¹ Probe A AAGGAGAAATGCTGGCATAGAGCAGC-TAMRAhGAPDH Forward SEQ ID NO. 4: VIC-CGCCTGGTCACCAGGGCTGCT- LTI² Probe TAMRAhGAPDH Forward SEQ ID NO. 5: CAACGGATTTGGTCGTATTGG LTI² PrimerhGAPDH Reverse SEQ ID NO. 6: TGATGGCAACAATATCCACTTTACC LTI² Primer¹Primers and probe designed by PTC Therapeutics, Inc.; ²Commerciallyavailable from Life Technologies, Inc. (formerly Invitrogen).

The SMN forward and reverse primers are used at final concentrations of0.4 μM. The SMN probe is used at a final concentration of 0.15 μM. TheGAPDH primers are used at final concentrations of 0.2 μM and the probeat 0.15 μM.

The SMN2-minigene GAPDH mix (15 μL total volume) is prepared bycombining 7.5 μL of 2×RT-PCR buffer, 0.4 μL of 25×RT-PCR enzyme mix,0.75 μL of 20×GAPDH primer-probe mix, 4.0075 μL of water, 2 μL of10-fold diluted cell lysate, 0.06 μL of 100 μM SMN forward primer, 0.06μL of 100 μM SMN reverse primer, and 0.225 μL of 100 μM SMN probe.

PCR is carried out at the following temperatures for the indicated time:Step 1: 48° C. (15 min); Step 2: 95° C. (10 min); Step 3: 95° C. (15sec); Step 4: 60° C. (1 min); then repeat Steps 3 and 4 for a total of40 cycles.

Each reaction mixture contains both SMN2-A minigene and GAPDHprimers/probe sets (multiplex design), allowing simultaneous measurementof the levels of two transcripts.

Two SMN spliced products are generated from the SMN2 minigene. The firstspliced product containing exon 7, corresponding to full length SMN2mRNA, is referred to herein using the term “SMN2 minigene FL.” Thesecond spliced product lacking exon 7 is referred to herein using theterm “SMN2 minigene Δ7.”

The increase of SMN2 minigene FL mRNA relative to that in cells treatedwith vehicle control is determined from real-time PCR data using amodified ΔΔCt method (as described in Livak and Schmittgen, Methods,2001, 25:402-8). The amplification efficiency (E) is calculated from theslope of the amplification curve for SMN2 minigene FL and GAPDHindividually. The abundances of SMN2 minigene FL and GAPDH are thencalculated as (1+E)^(−Ct) where Ct is the threshold value for eachamplicon. The abundance of SMN2 minigene FL is normalized to GAPDHabundance. The normalized SMN2 minigene FL abundance from testcompound-treated samples is then divided by normalized SMN2 minigene FLabundance from vehicle-treated cells to determine the level of SMN2 FLmRNA relative to vehicle control.

Results.

As seen in FIG. 3, cells treated with Compound 6 (FIG. 3a ) and Compound170 (FIG. 3b ) increased SMN2 minigene FL mRNA at low concentrations.The two test compounds fully restored exon 7 inclusion relative tountreated cells.

For compounds of Formula (I) or a form thereof disclosed herein, Table 4provides the EC_(1.5x) for production of full length SMN2 mRNA that wasobtained from the 7-point concentration data generated for each testcompound according to the procedure of Biological Example 2. The term“EC_(1.5x) for production of full length SMN2 mRNA” is defined as thatconcentration of test compound that is effective in increasing theamount of full length SMN2 mRNA to a level 1.5-fold greater relative tothat in vehicle-treated cells. An EC_(1.5x) for production of fulllength SMN2 mRNA between >3 μM and ≤30 μM is indicated by one star (*),an EC_(1.5x) between >1 μM and ≤3 μM is indicated by two stars (**), anEC_(1.5x) between >0.3 μM and ≤1 μM is indicated by three stars (***),an EC_(1.5x) between >0.1 μM and ≤0.3 μM is indicated by four stars(****) and an EC_(1.5x)≤0.1 μM is indicated by five stars (*****).

TABLE 4 Cpd EC_(1.5x) 1 *** 2 ** 3 *** 4 ** 5 * 6 ***** 7 *** 8 **** 9** 10 ** 11 *** 12 *** 13 ** 14 ** 15 ** 16 ** 17 ** 18 *** 19 ** 20 **21 * 22 *** 23 * 24 ** 25 ** 26 * 27 * 28 * 29 * 30 ***** 31 ** 32 ** 33** 34 ** 35 * 36 * 37 ** 38 * 39 * 40 * 41 *** 42 ** 43 **** 44 ** 45 *46 ** 47 ** 48 * 49 * 50 * 51 * 52 * 53 ** 54 ** 55 ** 56 ** 57 * 58 *59 ** 60 ** 61 *** 62 **** 63 ** 64 * 65 * 66 *** 67 **** 68 **** 69 ***70 ** 71 ** 72 ***** 73 * 74 ***** 75 ***** 76 *** 77 *** 78 ** 79 ****80 ** 81 *** 82 ** 83 *** 84 ** 85 ** 86 **** 87 **** 88 ** 89 ** 90 **91 ** 92 ** 93 ** 94 ** 95 ** 96 *** 97 ** 98 ** 99 *** 100 *** 101 ***102 *** 103 *** 104 *** 105 **** 106 *** 107 *** 108 **** 109 ***** 110**** 111 **** 112 *** 113 ** 114 ** 115 ***** 116 **** 117 ***** 118**** 119 **** 120 ***** 121 ***** 122 ** 123 ** 124 *** 125 *** 126 ****127 *** 128 *** 129 *** 130 ** 131 ***** 132 ***** 133 ***** 134 *****135 ***** 136 ***** 137 **** 138 **** 139 ** 140 ** 141 ***** 142 ***143 ***** 144 ***** 145 ** 146 ** 147 ** 148 **** 149 *** 150 *** 151**** 152 **** 153 *** 154 ** 155 **** 156 *** 157 ** 158 ** 159 ** 160***** 161 *** 162 *** 163 ** 164 *** 165 ** 166 *** 167 ***** 168 ***169 ***** 170 ***** 171 ***** 172 ***** 173 *** 174 ** 175 ***** 176 ***177 **** 178 *** 179 *** 180 ** 181 ** 182 *** 183 ** 184 ** 185 *****186 ***** 187 ** 188 **** 189 *** 190 *** 191 ** 192 ** 193 ***** 194***** 195 ***** 196 ***** 197 **** 198 ***** 199 *** 200 ** 201 *****202 *** 203 ** 204 ***** 205 *** 206 ** 207 ***** 208 ***** 209 *****210 ***** 211 ***** 212 **** 213 **** 214 *** 215 *** 216 *** 217 ***218 **** 219 ***** 220 *** 221 ***** 222 *** 223 *** 224 *** 225 ** 226*** 227 ** 228 ** 229 *** 230 *** 231 *** 232 ** 233 *** 234 ***** 235*** 236 ** 237 ** 238 *** 239 ** 240 ***** 241 **** 242 ***** 243 *****244 ***** 245 *** 246 ** 247 ***** 248 *** 249 *** 250 ***** 251 *****252 **** 253 ** 254 **** 255 *** 256 *** 257 ***** 258 ***** 259 *****260 **** 261 ***** 262 **** 263 *** 264 ***** 265 ** 266 ** 267 *****268 ***** 269 ***** 270 ***** 271 ***** 272 ***** 273 ***** 274 *****275 ***** 276 *** 277 ** 278 ** 279 **** 280 ** 281 **** 282 *** 283***** 284 *** 285 ***** 286 *** 287 ***** 288 ***** 289 ***** 290 *****291 ***** 292 ***** 293 ***** 294 ***** 295 ***** 296 ***** 297 *****298 *** 299 ***** 300 ***** 301 ** 302 ***** 303 ***** 304 ***** 305***** 306 ***** 307 ***** 308 ***** 309 ***** 310 ***** 311 **** 312***** 313 ** 314 ***** 315 ***** 316 **** 317 *** 318 ***** 319 *****320 *** 321 ** 322 ***** 323 **** 324 *** 325 *** 326 ** 327 ***** 328***** 329 ***** 330 **** 331 ***** 332 *** 333 **** 334 ***** 335 *****336 **** 337 ***** 338 ***** 339 ***** 340 ***** 341 *** 342 ***** 343***** 344 **** 345 ***** 346 ***** 347 ***** 348 **** 349 ***** 350***** 351 ***** 352 ***** 353 **** 354 ***** 355 ***** 356 ***** 357**** 358 ***** 359 ***** 360 ** 361 **** 362 *** 363 *** 364 ** 365 ****366 ***** 367 ***** 368 ***** 369 ***** 370 **** 371 **** 372 ***** 373***** 374 ***** 375 ***** 376 ***** 377 *** 378 ***** 379 **** 380 ****381 **** 382 ***** 383 *** 384 ***** 385 ***** 386 *** 387 *** 388 *****389 ** 390 *** 391 ** 392 **** 393 ***** 394 **** 395 *** 396 **** 397***** 398 *** 399 *** 400 **** 401 **** 402 ***** 403 ***** 404 *** 405**** 406 *** 407 ***** 408 ***** 409 ***** 410 ***** 411 ***** 412 *****413 ***** 414 ***** 415 ***** 416 ***** 417 **** 418 ***** 419 **** 420***** 421 ***** 422 ***** 423 ***** 424 ***** 425 ***** 426 *** 427 **428 *** 429 ***** 430 ***** 431 ***** 432 ***** 433 ***** 434 *** 435**** 436 *** 437 **** 438 ***** 439 **** 440 ***** 441 ***** 442 *****443 ***** 444 *** 445 ***** 446 ***** 447 **** 448 ***** 449 ***** 450*** 451 ***** 452 ***** 453 ***** 454 ***** 455 **** 456 **** 457 *****458 ***** 459 ***** 460 **** 461 *** 462 ***** 463 ***** 464 **** 465*** 466 ***** 467 ***** 468 ***** 469 **** 470 ***** 471 ***** 472 *****473 ***** 474 ***** 475 *** 476 ***** 477 ***** 478 ***** 479 ***** 480***** 481 ***** 482 ***** 483 ***** 484 ***** 485 ***** 486 ***** 487**** 488 ***** 489 **** 490 ***** 491 *** 492 *** 493 ***** 494 *****495 ***** 496 ***** 497 ***** 498 ***** 499 ***** 500 **** 501 **** 502***** 503 ***** 504 ***** 505 ***** 506 ***** 507 **** 508 ***** 509***** 510 ***** 511 ***** 512 ***** 513 **** 514 **** 515 ***** 516***** 517 ***** 518 ***** 519 ***** 520 **** 521 **** 522 ***** 523***** 524 **** 525 **** 526 *** 527 ***** 528 ***** 529 ***** 530 *****531 **** 532 ***** 533 ***** 534 ***** 535 ***** 536 ***** 537 ***** 538***** 539 ***** 540 ***** 541 **** 542 ***** 543 ***** 544 ***** 545**** 546 ***** 547 ***** 548 ***** 549 ***** 550 ***** 551 **** 552 ***553 **** 554 **** 555 ** 556 *** 557 ** 558 ** 559 ** 560 ** 561 *****562 *** 563 **** 564 ** 565 ***** 566 ***** 567 **** 568 ***** 569 *****570 *** 571 *** 572 *** 573 *** 574 *** 575 *** 576 ***** 577 ***** 578***** 579 **** 580 ***** 581 **** 582 ***** 583 ***** 584 ***** 585***** 586 **** 587 ***** 588 ***** 589 **** 590 *** 591 *** 592 **** 593***** 594 **** 595 ***** 596 ***** 597 **** 598 **** 599 ***** 600 ****601 ***** 602 ***** 603 **** 604 *** 605 *** 606 ***** 607 ***** 608**** 609 ***** 610 ***** 611 *** 612 ***** 613 ***** 614 ***** 615 *****616 ***** 617 ***** 618 ***** 619 **** 620 *** 621 *** 622 ** 623 *****624 ***** 625 ** 626 *** 627 **** 628 *** 629 ***** 630 ***** 631 ****632 ***** 633 ***** 634 ***** 635 ***** 636 ***** 637 ***** 638 *****639 ***** 640 ***** 641 ***** 642 ***** 643 **** 644 **** 645 ***** 646*** 647 ***** 648 ***** 649 ***** 650 ***** 651 ***** 652 ***** 653***** 654 ***** 655 ***** 656 ***** 657 ***** 658 ***** 659 ***** 660***** 661 ***** 662 ***** 663 ***** 664 *** 665 **** 666 **** 667 *****668 ***** 669 ***** 670 ***** 671 ***** 672 ***** 673 ***** 674 *****675 ***** 676 ***** 677 ***** 678 ***** 679 ***** 680 ***** 681 *****682 *** 683 ***** 684 **** 685 **** 686 *** 687 ***** 688 ** 689 ****690 ***** 691 ***** 692 **** 693 ** 694 ***** 695 ***** 696 ***** 697***** 698 ***** 699 ***** 700 ***** 701 ***** 702 ***** 703 ***** 704**** 705 ***** 706 ***** 707 ***** 708 ***** 709 ***** 710 ***** 711***** 712 ***** 713 ***** 714 ***** 715 ***** 716 ***** 717 **** 718***** 719 ***** 720 ***** 721 ***** 722 ***** 723 ***** 724 *** 725 ****726 *** 727 ***** 728 **** 729 **** 730 ***** 731 ***** 732 *** 733***** 734 ***** 735 ***** 736 ***** 737 ***** 738 ***** 739 ***** 740*** 741 ***** 742 **** 743 ***** 744 ***** 745 ***** 746 ***** 747 *****748 ***** 749 ***** 750 ***** 751 ***** 752 ***** 753 ***** 754 *****755 ***** 756 ***** 757 *** 758 *** 759 **** 760 ***** 761 ***** 762***** 763 ***** 764 ** 765 ** 766 ***** 767 ***** 768 ***** 769 **** 770***** 771 ***** 772 ***** 773 ***** 774 ***** 775 *** 776 ** 777 ** 778***** 779 ***** 780 ***** 781 ***** 782 ***** 783 ***** 784 **** 785***** 786 **** 787 ***** 788 ***** 789 ***** 790 ***** 791 ***** 792***** 793 ***** 794 ***** 795 ***** 796 ***** 797 ** 798 ***** 799 *****800 ***** 801 **** 802 ** 803 ***** 804 ***** 805 **** 806 ***** 807***** 808 ***** 809 ***** 810 ***** 811 *** 812 ***** 813 ***** 814***** 815 ***** 816 ***** 817 ***** 818 **** 819 ***** 820 ***** 821***** 822 **** 823 * 824 *** 825 *** 826 **** 827 ***** 828 ***** 829**** 830 ***** 831 **** 832 **** 833 ***** 834 ***** 835 *****

Example 3

Endogenous SMN2 mRNA RT-qPCR Splicing Assay in Cultured Cells

The reverse transcription-quantitative PCR-based (RT-qPCR) assay is usedto quantify the levels of the full length and Δ7 SMN2 mRNA in primarycells and cell lines containing the SMN2 gene treated with a testcompound.

Materials

Material Source SMA Type 1 human cells GM03813 (Coriell Institute)Cells-To-Ct lysis buffer Life Technologies, Inc. (formerly AppliedBiosystems) Catalog No.: 4399002 DMEM Life Technologies, Inc. (formerlyInvitrogen) Catalog No.: 11960-044 96-well flat- Becton DickinsonCatalog # 353072 bottom plates RT-PCR Enzyme Mix Life Technologies, Inc.(formerly Applied Biosystems) Part No.: 4388520 (also included inAgPath-ID Kit Catalog No.: 4387391) RT-PCR buffer Life Technologies,Inc. (formerly Applied Biosystems) Part No.: 4388519 (also included inAgPath-ID Kit Catalog No.: 4387391) AgPath-ID One-Step RT- LifeTechnologies, Inc. (formerly Applied PCR Kit Biosystems) Catalog No.:4387391 Thermocycler Life Technologies, Inc. (formerly AppliedBiosystems) 7900HT

Protocol.

GM03813 SMA patient cells (5,000 cells/well) are seeded in 200 μL ofcell culture medium (DMEM plus 10% FBS) in 96-well flat-bottom platesand the plate is immediately swirled to ensure proper dispersal ofcells, forming an even monolayer of cells. Cells are allowed to attachfor at least 4-6 hrs. Test compounds are serially diluted 3.16-fold in100% DMSO to generate a 7-point concentration curve. A solution of testcompound (1 μL, 200× in DMSO) is added to each test well and 1 μL DMSOis added to each control well. The plate is incubated for 24 hrs in acell culture incubator (37° C., 5% CO₂, 100% relative humidity). Thecells are then lysed in Cells-To-Ct lysis buffer and the lysate isstored at −80° C.

SMN2-specific spliced products and GAPDH mRNA are identified using thefollowing primers and probes in Table 5. Primer SMN FL Forward B (SEQ IDNO. 7) hybridizes to a nucleotide sequence in exon 7 (nucleotide 32 tonucleotide 54) and exon 8 (nucleotide 1 to nucleotide 4), primer SMN Δ7Forward B (SEQ ID NO. 8) hybridizes to a nucleotide sequence in exon 6(nucleotide 87 to nucleotide 111) and exon 8 (nucleotide 1 to nucleotide3), primer SMN Reverse B (SEQ ID NO. 9) hybridizes to a nucleotidesequence in exon 8 (nucleotide 39 to nucleotide 62), probe SMN Probe B(SEQ ID NO. 10) hybridizes to a nucleotide sequence in exon 8(nucleotide 7 to nucleotide 36). These primers and probes hybridize tonucleotide sequences common to human SMN1 and SMN2 mRNA. Since the SMApatient cells used in Example 3 contain only the SMN2 gene, RT-qPCR canquantify only SMN2 full-length and Δ7 mRNA.

TABLE 5 Primer/Probe Sequence Source SMN FL ForwardSEQ ID NO. 7: GCTCACATTCCTTAAATTAAGGAGAAA PTC¹ Primer B SMN Δ7 ForwardSEQ ID NO. 8: TGGCTATCATACTGGCTATTATATGGAA PTC¹ Primer B SMN ReverseSEQ ID NO. 9: TCCAGATCTGTCTGATCGTTTCTT PTC¹ Primer B SMN ForwardSEQ ID NO. 10: 6FAM- PTC¹ Probe B CTGGCATAGAGCAGCACTAAATGACACCAC-TAMRAhGAPDH Forward SEQ ID NO. 4: VIC-CGCCTGGTCACCAGGGCTGCT- LTI² Probe TAMRAhGAPDH Forward SEQ ID NO. 5: CAACGGATTTGGTCGTATTGG LTI² PrimerhGAPDH Reverse SEQ ID NO. 6: TGATGGCAACAATATCCACTTTACC LTI² Primer¹Primers and probe designed by PTC Therapeutics, Inc.; ²Commerciallyavailable from Life Technologies, Inc. (formerly Invitrogen).

The SMN forward and reverse primers are used at final concentrations of0.4 μM. The SMN probe is used at a final concentration of 0.15 μM. GAPDHprimers are used at final concentrations of 0.1 μM and the probe at0.075 μM.

The SMN-GAPDH mix (10 μL total volume) is prepared by combining 5 μL of2×RT-PCR buffer, 0.4 μL of 25× RT-PCR enzyme mix, 0.25 μL of 20× GAPDHprimer-probe mix, 1.755 μL water, 2.5 μL of cell lysate, 0.04 μL of 100μM SMN FL or SMN Δ7 forward primer, 0.04 μL of 100 μM SMN reverseprimer, and 0.015 μL of 100 μM probe.

PCR is carried out at the following temperatures for the indicated time:Step 1: 48° C. (15 min); Step 2: 95° C. (10 min); Step 3: 95° C. (15sec); Step 4: 60° C. (1 min); then, repeat Steps 3 and 4 for a total of40 cycles.

Each reaction mixture contains either SMN2 FL and GAPDH or SMN2 Δ7 andGAPDH primers/probe sets (multiplex design), allowing simultaneousmeasurement of the levels of two transcripts.

The endogenous SMN2 gene gives rise to two alternatively spliced mRNA.The full length SMN2 mRNA that contains exon 7 is referred to hereinusing the term “SMN2 FL.” The truncated mRNA that lacks exon 7 isreferred to herein using the term “SMN2 Δ7.”

The increase of SMN2 FL and decrease in SMN2 Δ7 mRNA relative to thosein cells treated with vehicle control are determined from real-time PCRdata using a modified ΔΔCt method (as described in Livak and Schmittgen,Methods, 2001, 25:402-8). The amplification efficiency (E) is calculatedfrom the slope of the amplification curve for SMN2 FL, SMN2 Δ7, andGAPDH individually. The abundances of SMN2 FL, SMN2 Δ7, and GAPDH arethen calculated as (1+E)^(−Ct), where Ct is the threshold value for eachamplicon. The abundances of SMN2 FL and SMN2 Δ7 are normalized to GAPDHabundance. The normalized SMN2 FL and SMN2 Δ7 abundances from testcompound-treated samples are then divided by normalized SMN2 FL and SMN2Δ7 abundances, respectively, from vehicle-treated cells to determine thelevels of SMN2 FL and SMN2 Δ7 mRNA relative to vehicle control.

Results.

As seen in FIG. 4, cells treated with increasing concentrations ofCompound 6 (FIG. 4a ) and Compound 170 (FIG. 4b ) contain progressivelymore SMN2 FL mRNA and less SMN2 Δ7 mRNA than those treated with vehicle,indicating a correction of SMN2 alternative splicing.

Example 4

Endogenous SMN2 mRNA End-Point Semi-Quantitative RT-PCR Splicing Assayin Cultured Cells

The endpoint reverse transcription-PCR splicing assay is used tovisualize and quantify the levels of the full length and Δ7 SMN2 mRNA inprimary cells and cell lines containing the SMN2 gene treated with atest compound.

Materials

Material Source SMA Type 1 human cells GM03813 (Coriell Institute)Cells-To-Ct lysis buffer Life Technologies, Inc. (formerly AppliedBiosystems) Catalog No.: 4399002 DMEM Life Technologies, Inc. (formerlyInvitrogen) Catalog No.: 11960-044 96-well flat-bottom plates BectonDickinson Catalog No.: 353072 Platinum Taq HiFi DNA Life Technologies,Inc. (formerly Polymerase Super Mix Invitrogen) Catalog No.: 11304-016iScript RT enzyme Kit BioRad: Catalog No.: 170-8890 Ethidium bromide 2%Life Technologies, Inc. (formerly agarose E gels 48-Well Invitrogen)Catalog No.: G8008-02 Double Comb Gel Documentation System UVP Gel DocIt 310 Imaging system

Protocol.

GM03813 SMA patient cells (5,000 cells/well) are seeded in 200 μL ofcell culture medium (DMEM plus 10% FBS) in 96-well flat-bottom platesand the plate is immediately swirled to ensure proper dispersal ofcells, forming an even monolayer of cells. Cells are allowed to attachfor at least 4-6 hrs. Test compounds are serially diluted 3.16-fold in100% DMSO to generate a 7-point concentration curve. A solution of testcompound (1 μL, 200× in DMSO) is added to each test well and 1 μL DMSOis added to each control well. The plate is incubated for 24 hrs in acell culture incubator (37° C., 5% CO₂, 100% relative humidity). Thecells are then lysed in Cells-To-Ct lysis buffer and the lysate isstored at −80° C.

SMN FL and Δ7 mRNA are identified using the following primers in Table6. These primers hybridize to a nucleotide sequence in exon 6 (SMNForward C, SEQ ID NO. 11) (nucleotide 43 to nucleotide 63) and exon 8(SMN Reverse C, SEQ ID NO. 12) (nucleotide 51 to nucleotide 73) commonto human SMN1 and SMN2 mRNA. Since the SMA patient cells used in Example4 contain only the SMN2 gene, RT-PCR can visualize and quantify onlySMN2 full-length and SMN2 Δ7 mRNA.

TABLE 6 Primer Sequence Source SMN Forward CSEQ ID NO. 11: GATGCTGATGCTTTGGGAAGT PTC¹ SMN Reverse CSEQ ID NO. 12: CGCTTCACATTCCAGATCTGTC PTC¹ ¹Primers designed by PTCTherapeutics, Inc.

To synthesize cDNA, 5 μL of lysate, 4 μL of 5× iScript reaction mix, 1μL of reverse transcriptase, and 10 μL of water are combined andincubated 5 min at 25° C. followed by 30 min at 42° C., followed by 5min at 85° C. The cDNA solution is stored at −20° C.

To perform endpoint PCR, 5 μL of cDNA, 0.2 μL of 100 μM forward primer,0.2 μL of 100 μM reverse primer, and 22.5 μL of polymerase super mix arecombined in a 96 well semiskirted PCR plate. PCR is carried out at thefollowing temperatures for the indicated time: Step 1: 94° C. (2 min),Step 2: 94° C. (30 sec), Step 3: 55° C. (30 sec), Step 4: 68° C. (1min), then repeat Steps 2 to 4 for a total of 33 cycles, then hold at 4°C.

10 μL of each PCR sample is electrophoretically separated on a 2%agarose E-gel for 14 minutes stained with double-stranded DNA (dsDNA)staining reagents (e.g., ethidium bromide) and visualized using a gelimager.

Results.

As seen in FIG. 5, cells treated with increasing concentrations ofCompound 6 (FIG. 5a ) or Compound 170 (FIG. 5b ) contain progressivelymore SMN2 FL mRNA and less SMN2 Δ7 mRNA, indicating a correction of SMN2alternative splicing.

Example 5

SMN2 mRNA RT-qPCR Splicing Assay in Animal Tissues

The reverse transcription-quantitative PCR-based (RT-qPCR) assay is usedto quantify the levels of the full length and Δ7 SMN2 mRNA in tissuesfrom mice treated with test compound.

Materials

Material Source Tissues from C/C- The Jackson Laboratory, strain alleleSMA mice No.: 008714 (B6.129-Smn1^(tm5(Smn1/SMN2)Mrph)/J) Tissues fromΔ7 SMA The Jackson Laboratory, strain No.: 005025 mice(FVB.Cg-Tg(SMN2*delta7)4299Ahmb Tg(SMN2)89Ahmb Smn1^(tm1Msd)/J) RT-PCREnzyme Mix Life Technologies, Inc. (formerly Applied Biosystems) PartNo.: 4388520 (also included in AgPath-ID Kit Catalog No.: 4387391)RT-PCR buffer Life Technologies, Inc. (formerly Applied Biosystems) PartNo.: 4388519 (also included in AgPath-ID Kit Catalog No.: 4387391)AgPath-ID One-Step Life Technologies, Inc. (formerly Applied RT-PCR KitBiosystems) Catalog No.: 4387391 Mouse GAPDH Life Technologies, Inc.(formerly Applied primers and probes Biosystems) Catalog No.: 4352339EQIAzol Lysis Reagent Qiagen Catalog No.: 79306 RNeasy Lipid TissueQiagen Catalog No.: 74804 Mini Kit 5 mm Stainless Qiagen Catalog No.:69989 Steel Bead TissueLyzer II Qiagen Catalog No.: 85300 ThermocyclerLife Technologies, Inc. (formerly Applied Biosystems) 7900HT

Protocol.

C/C-allele SMA mice are treated by oral gavage two times per day (BID)for 10 days with test compounds re-suspended in 0.5% HPMC and 0.1%Tween-80. Tissue samples were collected and snap frozen for RNApurification.

Tissue samples (20-40 mg) are homogenized in QIAzol Lysis Reagent for 2minutes at 20 Hz in the TissueLyser II using one stainless steel bead.After addition of chloroform, the homogenate is separated into aqueousand organic phases by centrifugation. RNA partitioned to the upper,aqueous phase is extracted and ethanol is added to provide appropriatebinding conditions. The sample is then applied to the RNeasy spin columnfrom the RNeasy Mini Kit, where total RNA binds to the membrane. The RNAis eluted in RNase-free water then stored at −20° C. and subsequentlyanalyzed using the TaqMan RT-qPCR on the 7900HT Thermocycler. Total RNAis diluted ten fold and 2.5 μL of the diluted sample is added to theTaqMan RT-qPCR mixture.

SMN2 spliced products are identified using the following primers andprobe in Table 7. Primer SMN FL Forward B (SEQ ID NO. 7) hybridizes to anucleotide sequence in exons 7 and 8, primer SMN Δ7 Forward B (SEQ IDNO. 8) hybridizes to a nucleotide sequence in exons 6 and 8, primer SMNReverse B (SEQ ID NO. 9) hybridizes to a nucleotide sequence in exon 8,probe SMN Probe B (SEQ ID NO. 10) hybridizes to a nucleotide sequence inexon 8. These primers and probe hybridize to nucleotide sequences commonto human SMN1 and SMN2 mRNA. Since the SMA patient cells used in Example5 contain only the SMN2 gene, RT-qPCR can quantify only SMN2 full-lengthand Δ7 mRNA.

TABLE 7 Primer/Probe Sequence Source SMN FL ForwardSEQ ID NO. 7: GCTCACATTCCTTAAATTAAGGAGAAA PTC¹ Primer B SMN Δ7 ForwardSEQ ID NO. 8: TGGCTATCATACTGGCTATTATATGGAA PTC¹ Primer B SMN ReverseSEQ ID NO. 9: TCCAGATCTGTCTGATCGTTTCTT PTC¹ Primer B SMN ForwardSEQ ID NO. 10: 6FAM- PTC¹ Probe B CTGGCATAGAGCAGCACTAAATGACACCAC-TAMRA¹Primers and probe designed by PTC Therapeutics, Inc.

The SMN forward and reverse primers are used at final concentrations of0.4 μM. The SMN probe is used at a final concentration of 0.15 μM. TheSMN-GAPDH Mix (10 μL total volume) is prepared by combining 5 μL of 2×RT-PCR buffer, 0.4 μL of 25× RT-PCR enzyme mix, 0.5 μL of 20× GAPDHprimer-probe mix, 1.505 μL of water, 2.5 μL of RNA solution, 0.04 μL of100 μM forward primer, 0.04 μL of 100 μM reverse primer, and 0.015 μL of100 μM SMN probe.

Each PCR cycle was carried out at the following temperatures for theindicated time: Step 1: 48° C. (15 min); Step 2: 95° C. (10 min); Step3: 95° C. (15 sec); Step 4: 60° C. (1 min); then, repeat Steps 3 and 4for a total of 40 cycles.

Each reaction mixture contains either SMN2 FL and mGAPDH or SMN2 Δ7 andmGAPDH primers/probe sets (multiplex design), allowing simultaneousmeasurement of the levels of two transcripts.

The increase of SMN2 FL and decrease in SMN2 Δ7 mRNA relative to thosein tissues from animals treated with vehicle control are determined fromreal-time PCR data using a modified ΔΔCt method (as described in Livakand Schmittgen, Methods, 2001, 25:402-8). The amplification efficiency(E) is calculated from the slope of the amplification curve for SMN2 FL,SMN2 Δ7, and GAPDH individually. The abundances of SMN2 FL, SMN2 Δ7, andGAPDH are then calculated as (1+E)^(−Ct), where Ct is the thresholdvalue for each amplicon. The abundances of SMN2 FL and SMN2 Δ7 arenormalized to GAPDH abundance. The normalized SMN2 FL and SMN2 Δ7abundances from test compound-treated samples are then divided bynormalized SMN2 FL and SMN2 Δ7 abundances, respectively, fromvehicle-treated cells to determine the levels of SMN2 FL and SMN2 Δ7mRNA relative to vehicle control.

Results.

As seen in FIG. 6, tissues of animals treated with Compound 6 (FIG. 6a )and Compound 170 (FIG. 6b ) contain substantially more SMN2 FL mRNA andless SMN2 Δ7 mRNA than those treated with vehicle, indicating acorrection of SMN2 alternative splicing.

Example 6

Endogenous SMN2 mRNA End-Point Semi-Quantitative RT-PCR Splicing Assayin Animal Tissues

The endpoint reverse transcription-PCR (RT-PCR) splicing assay is usedto quantify the levels of the full length and Δ7 SMN2 mRNA in tissuesfrom mice treated with test compound.

Materials

Material Source Tissues from C/C-allele The Jackson Laboratory, strainNo.: 008714 SMA mice (B6.129-Smn1^(tm5(Smn1/SMN2)Mrph)/J) Tissues fromΔExon7 SMA The Jackson Laboratory, strain No.: 005025 mice(FVB.Cg-Tg(SMN2*delta7)4299Ahmb Tg(SMN2)89Ahmb Smn1^(tm1Msd)/J) QiagenRNeasy lipid Kit Qiagen Catalog No.: 74804 Platinum Taq HiFi DNA LifeTechnologies, Inc. (formerly Polymerase Super Mix Invitrogen) CatalogNo.: 11304-016 iScript RT enzyme Kit BioRad Catalog No.: 170-8890Twin.tec 96-Well Eppendorf Catalog No.: 951020389 Semiskirted PCR PlateEthidium bromide Life Technologies, Inc. (formerly 2% agarose E gels48-Well Double Comb Invitrogen) Catalog No.: G8008-02 Gel DocumentationSystem UVP Gel Doc It 310 Imaging system

Protocol.

C/C-allele SMA mice are treated by oral gavage BID for 10 days with testcompounds in 0.5% HPMC and 0.1% Tween-80. Tissue samples are collectedand snap frozen for RNA purification.

Tissue samples (20-40 mg) are homogenized in QIAzol Lysis Reagent for 2minutes at 20 Hz in the TissueLyser II using one stainless steel bead.After addition of chloroform, the homogenate is separated into aqueousand organic phases by centrifugation. RNA partitioned to the upper,aqueous phase is extracted and ethanol is added to provide appropriatebinding conditions. The sample is then applied to the RNeasy spin columnfrom the RNeasy Mini Kit, where total RNA binds to the membrane. The RNAis eluted in RNase-free water then stored at −20° C.

SMN2 spliced products are identified using the following amplificationprimers in Table 8. These primers hybridize to a nucleotide sequence inexon 6 (SMN Forward D, SEQ ID NO. 13) (nucleotide 22 to nucleotide 46)and exon 8 (SMN Reverse C, SEQ ID NO. 12), common to human SMN1 and SMN2mRNA.

TABLE 8 Primer Sequence Source SMN Forward DSEQ ID NO. 13: ATATGTCCAGATTCTCTTGATGATG PTC¹ SMN Reverse CSEQ ID NO. 12: CGCTTCACATTCCAGATCTGTC PTC¹ ¹Primers designed by PTCTherapeutics, Inc.

To synthesize cDNA, combine 1 μL of RNA solution (25-50 ng), 4 μL of 5×iScript reaction mix, 1 μL of reverse transcriptase, and 10 μL of waterare combined and incubates 25° C. for 5 min followed by 42° C. for 30min followed by 85° C. for 5 min. The cDNA solution is stored at −20° C.

To perform endpoint PCR, 5 μL of cDNA, 0.2 μL of 100 μM forward primer,0.2 μL of 100 μM reverse primer, and 22.5 μL of polymerase super mix arecombined in a 96 well semiskirted PCR plate. PCR is carried out at thefollowing temperatures for the indicated time: Step 1: 94° C. (2 min),Step 2: 94° C. (30 sec), Step 3: 55° C. (30 sec), Step 4: 68° C. (1min), then repeat Steps 2 to 4 for a total of 33 cycles, then hold at 4°C.

10 μL of each PCR sample is electrophoretically separated on a 2%agarose E-gel for 14 minutes stained with dsDNA staining reagents (e.g.,ethidium bromide) and visualized using a gel imager.

Results.

As seen in FIG. 7, tissues from mice treated with increasingconcentrations of Compound 6 (FIG. 7a ) and Compound 170 (FIG. 7b )contain progressively more SMN2 FL mRNA and less SMN2 Δ7 mRNA,indicating a correction of SMN2 alternative splicing.

Example 7

Smn Protein Assay in Cultured Cells

The SMN HTRF (homogeneous time resolved fluorescence) assay is used toquantify the level of Smn protein in SMA patient fibroblast cellstreated with test compounds. The results of the assay are shown in Table9.

Materials

Material Source SMA Type 1 human cells GM03813 (Coriell Institute)Protease inhibitor Roche Applied Science Catalog cocktail No.:11836145001 Anti-SMN d2 Blue cap Cisbio Catalog No.: 63IDC002-SMNAnti-SMN kryptate Red cap Cisbio Catalog No.: 63IDC002-SMN SMNreconstitution Cisbio Catalog No.: 63IDC002-SMN-Buffer buffer DMEM LifeTechnologies, Inc. (formerly Invitrogen) Catalog No.: 11960-044 RIPALysis Buffer 20 mM Tris-HCl pH 7.5, 150 mM NaCl, 1 mM EDTA, 1% NP-40, 1%Sodium deoxycholate Diluent Buffer 20 mM Tris-HCl pH 7.5, 150 mM NaClEnvision Plate Reader Perkin Elmer Model No.: 2103

Protocol.

Cells are thawed and cultured in DMEM-10% FBS for 72 hours. Cells aretrypsinized, counted and re-suspended to a concentration of 25,000cells/mL in DMEM-10% FBS. The cell suspension is plated at 5,000 cellsper well in a 96 well microtiter plate and incubated for 3 to 5 hours.To provide a control signal, three (3) wells in the 96 well plate do notreceive cells and, thus, serve as Blank control wells. Test compoundsare serially diluted 3.16-fold in 100% DMSO to generate a 7-pointconcentration curve. 1 μL of test compound solution is transferred tocell-containing wells and cells are incubated for 48 hours in a cellculture incubator (37° C., 5% CO₂, 100% relative humidity). Triplicatesamples are set up for each test compound concentration. After 48 hours,the supernatant is removed from the wells and 25 μL of the RIPA lysisbuffer, containing protease inhibitors, is added to the wells andincubated with shaking at room temperature for 1 hour. 25 μL of thediluent is added and then 35 μL of the resulting lysate is transferredto a 384-well plate, where each well contains 5 μL of the antibodysolution (1:100 dilution of anti-SMN d₂ and anti-SMN kryptate in SMNreconstitution buffer). The plate is centrifuged for 1 minute to bringthe solution to the bottom of the wells, then incubated overnight atroom temperature. Fluorescence for each well of the plate at 665 nm and620 nm is measured on an EnVision multilabel plate reader(Perkin-Elmer).

The normalized fluorescence signal is calculated for each sample, Blankand vehicle control well by dividing the signal at 665 nm by the signalat 620 nm. Normalizing the signal accounts for possible fluorescencequenching due to the matrix effect of the lysate. The ΔF value (ameasurement of Smn protein abundance as a percent value) for each samplewell is calculated by subtracting the normalized average fluorescencefor the Blank control wells from the normalized fluorescence for eachsample well, then dividing this difference by the normalized averagefluorescence for the Blank control wells and multiplying the resultingvalue by 100. The ΔF value for each sample well represents the Smnprotein abundance from test compound-treated samples. The ΔF value foreach sample well is divided by the ΔF value for the vehicle controlwells to calculate the fold increase in Smn protein abundance relativeto the vehicle control.

Results.

As seen in FIG. 8, SMA Type 1 patient fibroblast cells treated withCompound 6 (FIG. 8a ) and Compound 170 (FIG. 8b ) show a dose dependentincrease in Smn protein expression as measured by the SMN HTRF assay.

For compounds of Formula (I) or a form thereof disclosed herein, Table 9provides the EC_(1.5x) for Smn protein expression that was obtained fromthe 7-point concentration data generated for each test compoundaccording to the procedure of Biological Example 7. The term “EC_(1.5x)for Smn protein expression” is defined as that concentration of testcompound that is effective in producing 1.5 times the amount of Smnprotein in an SMA patient fibroblast cell compared to the amountproduced from the DMSO vehicle control. An EC_(1.5x) for Smn proteinexpression between >3 μM and ≤10 μM is indicated by one star (*), anEC_(1.5x) between >1 μM and ≤3 μM is indicated by two stars (**), anEC_(1.5x) between >0.3 μM and ≤1 μM is indicated by three stars (***)and an EC_(1.5x)≤0.3 μM is indicated by four stars (****).

TABLE 9 Cpd EC_(1.5x) 3 ** 6 *** 8 ** 18 ** 20 ** 22 ** 24 * 30 ** 43 **61 *** 62 *** 66 * 67 *** 69 *** 71 * 72 *** 74 *** 75 **** 79 *** 82 **84 ** 85 * 86 **** 87 *** 90 * 95 ** 96 *** 99 *** 100 *** 102 *** 105*** 106 ** 109 **** 115 **** 116 * 117 **** 118 *** 119 *** 120 **** 121**** 127 * 129 * 130 * 131 ** 132 **** 133 **** 134 **** 135 **** 136**** 137 *** 138 *** 141 **** 143 **** 144 **** 148 ** 150 ** 152 ****160 *** 161 ** 162 ** 164 ** 167 ** 169 **** 170 **** 171 **** 172 ****175 *** 176 * 179 *** 180 ** 182 *** 186 *** 188 *** 189 *** 190 ** 191** 192 ** 193 **** 194 **** 195 *** 196 **** 197 **** 198 **** 199 **201 *** 204 **** 208 *** 209 **** 210 **** 211 **** 212 **** 213 ****214 ** 218 ** 219 **** 221 **** 224 *** 229 * 230 ** 231 ** 234 **** 235** 236 * 240 **** 241 **** 242 **** 243 **** 244 **** 247 **** 248 ***250 **** 251 **** 252 *** 254 ** 256 ** 257 ** 258 *** 259 *** 260 **261 **** 262 *** 263 *** 264 **** 267 **** 268 **** 269 **** 270 ****271 **** 272 **** 273 **** 274 **** 275 **** 283 **** 284 *** 285 ****286 *** 287 **** 288 **** 289 **** 290 **** 291 **** 292 **** 293 ****294 * 295 **** 296 **** 297 **** 299 **** 300 **** 302 **** 303 **** 304**** 305 **** 306 **** 307 **** 308 **** 309 **** 310 *** 312 **** 314*** 316 ** 317 ** 318 **** 319 **** 320 ** 322 *** 323 ** 326 ** 327**** 329 ** 331 **** 333 ** 334 **** 335 **** 336 **** 337 **** 338 ****339 **** 340 **** 341 *** 342 **** 343 **** 344 *** 346 **** 349 ** 350**** 351 **** 352 **** 354 *** 355 *** 356 *** 357 *** 358 ** 359 ** 366**** 367 * 368 *** 369 ** 370 *** 371 *** 372 **** 373 **** 374 **** 375**** 376 *** 377 ** 378 ** 380 *** 381 * 382 *** 384 **** 385 *** 393*** 396 *** 397 **** 398 ** 399 *** 400 *** 401 *** 402 ** 403 ** 404 **405 *** 406 * 409 **** 410 **** 412 **** 413 **** 414 *** 416 ** 417 **420 **** 422 ** 423 *** 424 **** 425 **** 426 *** 427 * 428 ** 429 ****430 **** 431 **** 432 **** 437 *** 438 **** 439 ** 440 **** 441 **** 442**** 443 **** 444 ** 445 *** 446 ** 448 **** 449 **** 451 *** 452 ****453 **** 454 **** 457 **** 458 *** 460 *** 461 ** 462 **** 463 *** 464** 466 *** 467 **** 468 *** 469 *** 470 **** 471 **** 472 **** 473 ****474 **** 475 ** 476 **** 477 **** 478 **** 480 **** 481 **** 482 * 484**** 485 **** 486 **** 487 **** 488 **** 489 ** 490 *** 491 ** 492 **493 *** 494 **** 495 **** 496 **** 497 *** 498 **** 499 **** 500 *** 501*** 502 **** 503 **** 504 **** 505 **** 506 **** 507 *** 508 *** 509 ***510 **** 511 ** 512 **** 513 **** 514 ** 515 **** 516 **** 517 **** 518**** 519 **** 520 **** 521 **** 522 *** 523 **** 524 *** 525 *** 526 **527 **** 528 **** 529 *** 530 **** 531 *** 532 **** 533 *** 534 **** 535*** 536 **** 537 **** 538 *** 539 **** 541 *** 542 *** 543 **** 544 ***545 **** 546 **** 547 **** 548 **** 549 **** 550 **** 551 **** 552 ***553 **** 554 **** 555 ** 556 ** 561 **** 563 **** 565 *** 566 **** 567*** 568 **** 569 **** 570 ** 571 ** 572 ** 573 ** 576 **** 577 **** 578**** 579 *** 580 *** 581 *** 582 **** 583 **** 584 **** 585 **** 586**** 587 **** 588 **** 589 *** 590 ** 591 ** 592 *** 593 **** 594 ***595 **** 596 **** 597 *** 598 *** 599 **** 600 ** 601 *** 602 **** 603*** 604 **** 605 *** 606 ** 607 **** 608 ** 609 **** 610 **** 612 ****613 **** 614 **** 615 **** 616 **** 617 **** 618 **** 619 *** 620 ** 621**** 622 ** 623 **** 624 **** 626 ** 627 ** 628 * 629 **** 630 **** 631*** 632 **** 633 **** 634 **** 635 **** 636 **** 637 **** 638 **** 639**** 640 **** 641 **** 642 **** 643 *** 644 *** 645 **** 646 ** 647 ****648 **** 649 **** 650 **** 651 **** 652 **** 653 **** 654 **** 655 ****656 **** 657 **** 658 **** 659 **** 660 **** 661 **** 662 **** 663 ****664 *** 665 **** 666 *** 667 **** 668 **** 669 **** 670 **** 671 ****672 **** 673 **** 674 **** 675 **** 676 *** 677 *** 678 **** 679 ****680 **** 681 **** 682 ** 683 *** 684 *** 685 ** 686 ** 687 **** 688 **689 *** 690 *** 691 **** 692 *** 693 ** 694 **** 695 **** 696 **** 697**** 698 **** 699 **** 700 **** 701 **** 702 **** 703 **** 704 **** 705**** 706 **** 707 **** 708 **** 709 **** 710 **** 711 **** 712 **** 713**** 714 **** 715 **** 716 *** 717 *** 718 *** 719 **** 720 **** 721**** 722 **** 723 **** 724 *** 725 *** 726 ** 727 **** 728 **** 729 ***730 **** 731 **** 732 *** 733 **** 734 **** 735 **** 736 **** 737 ****738 **** 739 **** 740 *** 741 **** 742 *** 743 **** 744 *** 745 **** 746**** 747 **** 748 **** 749 **** 750 **** 751 **** 752 **** 753 **** 754**** 755 **** 756 **** 757 *** 759 *** 760 **** 761 **** 762 **** 763**** 764 * 765 ** 766 **** 767 **** 768 **** 769 *** 770 *** 771 ****772 **** 773 **** 774 **** 777 ** 778 *** 779 **** 780 **** 781 **** 782**** 783 **** 784 *** 785 **** 786 *** 787 **** 788 **** 789 **** 790**** 791 **** 792 *** 793 **** 794 **** 795 **** 796 **** 797 * 798 ****799 **** 800 **** 801 *** 802 * 803 **** 804 **** 805 *** 806 **** 807**** 808 **** 809 **** 810 **** 811 *** 812 **** 813 **** 814 **** 815**** 816 **** 817 **** 818 *** 819 **** 820 **** 821 **** 822 *** 824 *825 ** 826 ** 827 *** 828 **** 829 ** 830 *** 831 ** 832 *** 833 ** 834**** 835 ****

For compounds of Formula (I) or a form thereof disclosed herein, Table10 provides the maximum fold (Fold) increase of Smn protein that wasobtained from the 7-point concentration data generated for each testcompound according to the procedure of Biological Example 7. A maximumfold increase of ≤1.2 is indicated by one star (*), a fold increasebetween >1.2 and ≤1.35 is indicated by two stars (**), a fold increasebetween >1.35 and ≤1.5 is indicated by three stars (***), a foldincrease between >1.5 and ≤1.65 is indicated by four stars (****) and afold increase >1.65 is indicated by five stars (*****).

TABLE 10 Cpd Fold 1 ** 2 ** 3 *** 4 * 5 * 6 **** 7 *** 8 **** 9 *** 10** 11 *** 12 *** 13 ** 14 *** 15 *** 16 * 17 * 18 **** 19 ** 20 ****21 * 22 *** 23 *** 24 *** 25 * 26 ** 27 * 28 ** 29 *** 30 **** 31 * 32 *33 * 34 ** 35 * 36 * 37 * 38 * 39 * 40 * 41 *** 42 * 43 *** 44 * 45 **46 *** 47 *** 48 * 49 * 50 ** 51 ** 52 * 53 * 54 * 55 * 56 * 57 * 58 *59 * 60 * 61 **** 62 ***** 63 ** 64 ** 65 ** 66 *** 67 *** 68 ** 69 ****70 * 71 **** 72 *** 73 ** 74 ***** 75 ***** 76 ** 77 ** 78 * 79 ****80 * 81 ** 82 ***** 83 * 84 ***** 85 *** 86 **** 87 **** 88 ** 89 *** 90*** 91 ** 92 ** 93 ** 94 *** 95 **** 96 **** 97 ** 98 *** 99 **** 100***** 101 *** 102 ***** 103 *** 104 *** 105 **** 106 **** 107 ** 108 ***109 **** 110 *** 111 *** 112 *** 113 *** 114 *** 115 **** 116 *** 117**** 118 ***** 119 ***** 120 ***** 121 ***** 122 *** 123 * 124 ** 125*** 126 ** 127 *** 128 *** 129 *** 130 *** 131 *** 132 ***** 133 ****134 ***** 135 **** 136 ***** 137 ***** 138 ***** 139 *** 140 *** 141***** 142 *** 143 ***** 144 **** 145 * 146 * 147 * 148 *** 149 ** 150**** 151 *** 152 ***** 153 ** 154 * 155 ** 156 *** 157 ** 158 * 159 ***160 *** 161 *** 162 **** 163 *** 164 **** 165 ** 166 ** 167 *** 168 *169 **** 170 ***** 171 ***** 172 ***** 173 ** 174 ** 175 **** 176 ***177 *** 178 ** 179 ***** 180 **** 181 * 182 **** 183 ** 184 ** 185 ***186 **** 187 ** 188 ***** 189 **** 190 **** 191 **** 192 ***** 193 *****194 ***** 195 **** 196 **** 197 ***** 198 **** 199 **** 200 * 201 ***202 ** 203 * 204 **** 205 ** 206 ** 207 *** 208 *** 209 **** 210 ****211 **** 212 **** 213 *** 214 **** 215 *** 216 *** 217 *** 218 *** 219**** 220 ** 221 ***** 222 *** 223 *** 224 **** 225 * 226 * 227 *** 228** 229 *** 230 **** 231 **** 232 * 233 * 234 ***** 235 **** 236 *** 237*** 238 ** 239 * 240 **** 241 ***** 242 **** 243 **** 244 **** 245 **246 * 247 ***** 248 **** 249 * 250 ***** 251 ***** 252 **** 253 * 254*** 255 ** 256 **** 257 **** 258 **** 259 **** 260 *** 261 **** 262***** 263 **** 264 ***** 265 *** 266 ** 267 ***** 268 ***** 269 *****270 **** 271 ***** 272 ***** 273 ***** 274 ***** 275 ***** 276 * 277 ***278 ** 279 ** 280 * 281 ** 282 ** 283 **** 284 **** 285 ***** 286 ****287 ***** 288 ***** 289 **** 290 ***** 291 ***** 292 **** 293 ***** 294*** 295 **** 296 ***** 297 ***** 298 *** 299 ***** 300 ***** 301 * 302***** 303 **** 304 ***** 305 ***** 306 ***** 307 **** 308 ***** 309 ****310 *** 311 ** 312 **** 313 * 314 **** 315 *** 316 ***** 317 **** 318***** 319 **** 320 **** 321 *** 322 **** 323 *** 324 *** 325 *** 326 ***327 **** 328 *** 329 **** 330 ** 331 ***** 332 * 333 **** 334 ***** 335***** 336 ***** 337 ***** 338 ***** 339 ***** 340 ***** 341 ***** 342***** 343 ***** 344 ***** 345 *** 346 **** 347 *** 348 ** 349 *** 350***** 351 ***** 352 **** 353 ** 354 **** 355 **** 356 **** 357 **** 358*** 359 *** 360 * 361 *** 362 *** 363 ** 364 * 365 *** 366 **** 367 ***368 **** 369 *** 370 ***** 371 **** 372 ***** 373 **** 374 ***** 375**** 376 *** 377 **** 378 **** 379 *** 380 **** 381 *** 382 **** 383 **384 ***** 385 ***** 386 * 387 ** 388 *** 389 ** 390 * 391 * 392 *** 393*** 394 ** 395 ** 396 **** 397 ***** 398 ***** 399 **** 400 **** 401***** 402 **** 403 **** 404 **** 405 **** 406 *** 407 *** 408 ** 409***** 410 ***** 411 *** 412 ***** 413 **** 414 ***** 415 *** 416 *** 417**** 418 *** 419 ** 420 **** 421 *** 422 *** 423 **** 424 ***** 425***** 426 ***** 427 *** 428 *** 429 **** 430 **** 431 ***** 432 *****433 *** 434 ** 435 *** 436 ** 437 **** 438 ***** 439 *** 440 **** 441***** 442 ***** 443 ***** 444 *** 445 *** 446 *** 447 * 448 ***** 449**** 450 ** 451 ***** 452 ***** 453 ***** 454 ***** 455 ** 456 *** 457***** 458 **** 459 *** 460 **** 461 **** 462 ***** 463 ***** 464 ****465 *** 466 ***** 467 ***** 468 **** 469 ***** 470 **** 471 ***** 472***** 473 ***** 474 **** 475 *** 476 ***** 477 **** 478 ***** 479 ** 480***** 481 **** 482 *** 483 ** 484 ***** 485 ***** 486 **** 487 **** 488**** 489 **** 490 ***** 491 **** 492 **** 493 **** 494 **** 495 *****496 ***** 497 **** 498 ***** 499 ***** 500 ***** 501 ***** 502 ***** 503***** 504 ***** 505 **** 506 **** 507 **** 508 **** 509 **** 510 *****511 **** 512 ***** 513 ***** 514 ***** 515 ***** 516 **** 517 ***** 518**** 519 ***** 520 **** 521 ***** 522 ***** 523 ***** 524 ***** 525***** 526 ***** 527 ***** 528 **** 529 ***** 530 ***** 531 ***** 532***** 533 ***** 534 ***** 535 ***** 536 **** 537 **** 538 **** 539 ****540 *** 541 ***** 542 ***** 543 ***** 544 **** 545 ***** 546 ***** 547***** 548 ***** 549 ***** 550 ***** 551 ***** 552 **** 553 ***** 554***** 555 *** 556 *** 557 * 558 ** 559 * 560 * 561 **** 562 ** 563 *****564 * 565 **** 566 ***** 567 **** 568 ***** 569 ***** 570 **** 571 ****572 **** 573 **** 574 ** 575 *** 576 ***** 577 ***** 578 ***** 579 *****580 ***** 581 ***** 582 ***** 583 ***** 584 ***** 585 ***** 586 *****587 **** 588 ***** 589 **** 590 **** 591 **** 592 ***** 593 ***** 594**** 595 **** 596 **** 597 **** 598 ***** 599 ***** 600 **** 601 ****602 **** 603 ***** 604 ***** 605 ***** 606 **** 607 ***** 608 **** 609***** 610 ***** 611 *** 612 ***** 613 ***** 614 ***** 615 **** 616 *****617 ***** 618 ***** 619 ***** 620 *** 621 ***** 622 **** 623 ***** 624***** 625 ** 626 ***** 627 **** 628 **** 629 ***** 630 ***** 631 *****632 ***** 633 ***** 634 ***** 635 ***** 636 ***** 637 ***** 638 *****639 ***** 640 **** 641 ***** 642 ***** 643 ***** 644 ***** 645 ***** 646***** 647 ***** 648 ***** 649 ***** 650 ***** 651 ***** 652 ***** 653***** 654 ***** 655 **** 656 **** 657 ***** 658 ***** 659 ***** 660 ****661 ***** 662 ***** 663 ***** 664 ***** 665 ***** 666 ***** 667 *****668 ***** 669 ***** 670 ***** 671 ***** 672 ***** 673 **** 674 ***** 675***** 676 ***** 677 ***** 678 ***** 679 ***** 680 ***** 681 ***** 682***** 683 ***** 684 ***** 685 **** 686 ***** 687 **** 688 *** 689 ****690 **** 691 ***** 692 ***** 693 **** 694 ***** 695 ***** 696 ***** 697***** 698 ***** 699 ***** 700 ***** 701 ***** 702 ***** 703 ***** 704**** 705 ***** 706 ***** 707 ***** 708 ***** 709 ***** 710 ***** 711***** 712 ***** 713 ***** 714 ***** 715 ***** 716 ***** 717 ***** 718**** 719 **** 720 ***** 721 ***** 722 ***** 723 ***** 724 ***** 725***** 726 **** 727 ***** 728 ***** 729 ***** 730 ***** 731 ***** 732**** 733 ***** 734 ***** 735 **** 736 ***** 737 ***** 738 ***** 739***** 740 ***** 741 ***** 742 ***** 743 ***** 744 *** 745 ***** 746***** 747 ***** 748 ***** 749 ***** 750 ***** 751 ***** 752 ***** 753***** 754 ***** 755 ***** 756 ***** 757 **** 758 *** 759 ***** 760 *****761 ***** 762 ***** 763 ***** 764 *** 765 **** 766 ***** 767 ***** 768***** 769 ***** 770 **** 771 ***** 772 ***** 773 ***** 774 ***** 775 ***776 ** 777 *** 778 ***** 779 ***** 780 ***** 781 ***** 782 ***** 783***** 784 **** 785 ***** 786 **** 787 ***** 788 ***** 789 ***** 790***** 791 ***** 792 ***** 793 ***** 794 ***** 795 ***** 796 ***** 797*** 798 ***** 799 ***** 800 ***** 801 ***** 802 ***** 803 ***** 804***** 805 ***** 806 ***** 807 ***** 808 ***** 809 ***** 810 ***** 811***** 812 ***** 813 ***** 814 ***** 815 ***** 816 **** 817 ***** 818***** 819 ***** 820 ***** 821 ***** 822 **** 823 ** 824 **** 825 *****826 ***** 827 ***** 828 ***** 829 ***** 830 ***** 831 **** 832 ***** 833***** 834 ***** 835 *****

Example 8 Gems Count (Smn-Dependent Nuclear Speckle Count) Assay

The level of Smn protein directly correlates with the amount of nuclearfoci, also known as gems, produced upon staining the cell with afluorescently labeled anti-Smn antibody (Liu and Dreyfuss, EMBO J.,1996, 15:3555). Gems are multi-protein complexes whose formation isnucleated by the Smn protein and the gems count assay is used toevaluate the level of Smn protein in the cell. As described herein, thegems count assay is used to quantify the level of Smn protein in SMApatient fibroblast cells treated with a test compound.

Materials

Material Source SMA Type 1 human cells GM03813 (Coriell Institute)Primary Antibody- mouse anti- Sigma Catalog No.: S2944 SMN clone 2B1Secondary Antibody- anti-mouse Life Technologies, Inc. (formerly AlexaFluor 555 Invitrogen) Catalog No.: A21422 Bovine Serum Albumin (BSA)Sigma Catalog No.: A3294 4% Paraformaldehyde Electron MicroscopySciences Catalog No.: 15710 Bortezomib LC Labs, Catalog No.: B-14080.05% Triton X-100 Sigma Catalog No.: 93443-100 mL Mounting medium-ProLong Gold Life Technologies, Inc. (formerly Antifade Reagent withDAPI Invitrogen) Catalog Nos.: P7481 and P36935 22x22 #1 sterile Coverslips Fisher Catalog No.: 12-548-B DMEM Life Technologies, Inc.(formerly Invitrogen) Catalog No.: 11960-044 PBS Life Technologies, Inc.(formerly Invitrogen) Catalog No.: 10010-031 Clear-coat nail polishRevlon brand Catalog No.: 1271-76 Zeiss Axovert 135 Fluorescence Zeissmicroscope

Protocol:

Cells are thawed and incubated in DMEM-10% FBS for 72 hours, thentrypsinized, counted and resuspended to 100,000 cells/mL in DMEM-10%FBS. The cell suspension (2 mL) is plated in a 6-well cell culture platewith a sterile cover slip and incubated for 3 to 5 hours. Test compoundsare serially diluted 3.16-fold in 100% DMSO to generate a 7-pointdilution curve. 10 μL of test compound solution is added to eachcell-containing well and incubated for 48 hours in a cell cultureincubator (37° C., 5% CO₂, 100% relative humidity). Duplicates are setup for each test compound concentration. Cells containing DMSO at afinal concentration of 0.5% are used as controls.

Cell culture medium is aspirated from the wells containing cover slipsand gently washed three times with cold PBS. The cells are fixed byincubation for 20 minutes at room temperature while in paraformaldehyde.The cells are then washed two times with cold PBS followed by incubationfor 5 minutes at room temperature with 0.05% Triton X-100 in PBS topermeabilize the cells. After the fixed cells are washed three timeswith cold PBS, they are blocked with 10% FBS for 1 hour. 60 μL ofprimary antibody diluted 1:1000 in blocking buffer is added and themixture is incubated for one hour at room temperature. The cells arewashed three times with PBS and 60 μL of secondary antibody diluted1:5000 in blocking buffer is added, then the mixture is incubated forone hour at room temperature. The cover slips are mounted onto theslides with the aid of mounting medium and allowed to dry overnight.Nail polish is applied to the sides of the cover slip and the slides arestored, protected from light. A Zeiss Axovert 135 with a 63×Plan-Apochromat, NA=1.4 objective is used for immunofluorescencedetection and counting. The number of gems is counted per ≥150 nucleiand % activation is calculated using DMSO and 10 nM bortezomib ascontrols. For each test compound, the cells are examined at allwavelengths to identify test compounds with inherent fluorescence.

Results.

As seen in FIG. 9, SMA Type 1 patient cells treated with Compound 6(FIG. 9a ) and Compound 170 (FIG. 9b ) contain progressively more gemsrelative to cells treated with DMSO.

Example 9 Smn Protein Assay in Human Motor Neurons

Smn immunofluorescent confocal microscopy is used to quantify the levelof Smn protein in human motor neurons treated with test compounds.

Protocol.

Human motor neurons derived from SMA iPS cells (Ebert et al., Nature,2009, 457:2770; and, Rubin et al., BMC Biology, 2011, 9:42) are treatedwith test compound at various concentrations for 72 hours. The level ofSmn protein in the cell nucleus is quantified using Smn immunostainingand confocal fluorescence microscopy essentially as described inMakhortova et al., Nature Chemical Biology, 2011, 7:544. The level ofSmn protein in compound-treated samples is normalized to that invehicle-treated samples and plotted as a function of the compoundconcentration.

Results.

As seen in FIG. 10, human motor neurons treated for 72 hours withincreasing concentrations of Compound 6 contain progressively more Smnprotein in the nucleus.

Example 10 Smn Protein Assay in Animal Tissues

This Smn protein assay compares tissues from test compound treated micewith those from DMSO vehicle treated mice to determine the increase inlevels of Smn protein produced from the human SMN2 gene.

Materials

Material Source Tissues from C/C-allele The Jackson Laboratory, strainNo.: 008714 SMA mice (B6.129-Smn1^(tm5(Smn1/SMN2)Mrph)/J) Tissues fromΔ7 SMA The Jackson Laboratory, strain No.: 005025 mice(FVB.Cg-Tg(SMN2*delta7)4299Ahmb Tg(SMN2)89Ahmb Smn1^(tm1Msd)/J) Proteaseinhibitor Roche Applied Science Catalog No.: cocktail 11836145001Anti-SMN d2 Blue cap Cisbio Catalog No.: 63IDC002-SMN Anti-SMN kryptateRed cap Cisbio Catalog No.: 63IDC002-SMN SMN reconstitution CisbioCatalog No.: 63IDC002-SMN-Buffer buffer RIPA Lysis Buffer 20 mM Tris-HClpH 7.5, 150 mM NaCl, 1 mM EDTA, 1% NP-40, 1% Sodium deoxycholate DiluentBuffer 20 mM Tris-HCl pH 7.5, 150 mM NaCl BCA protein assay Kit PierceCatalog No.: 23225 White 384 well plate Nunc Catalog No.: 351190Polypropylene V-bottom Falcon Catalog No.: 165195 plate Clear 96 wellpoly- Nunc Catalog No.: 442404 styrene plate 5 mm Stainless Steel QiagenCatalog No.: 69989 Beads Safe-Lock Tubes 2.0 mL Eppendorf Catalog No.:022363352 Twin.tec 96-Well Eppendorf Catalog No.: 951020389 SemiskirtedPCR Plate TissueLyzer II Qiagen Catalog No.: 85300 Envision Plate ReaderPerkin Elmer Model No.: 2103

Protocol.

The tissue samples in Safe-Lock tubes are weighed and the volume of RIPAbuffer containing the protease inhibitor cocktail is added based on theweight to volume ratios for each type of tissue: Brain (50 mg/mL),Muscle (50 mg/mL) and Spinal Cord (25 mg/mL).

Tissues are homogenized using the TissueLyzer by bead milling. 5 mmstainless steel beads are added to the sample and shaken vigorously for5 minutes at 30 Hz in the TissueLyzer. The samples are then centrifugedfor 20 minutes at 14,000× g in a microcentrifuge and the homogenatestransferred to the PCR plate. The homogenates are diluted in RIPA bufferto approximately 1 mg/mL for HTRF and approximately 0.5 mg/mL for totalprotein measurement using the BCA protein assay. For the SMN HTRF assay,35 μL of the tissue homogenate is transferred to a 384-well platecontaining 5 μL of the antibody solution (1:100 dilution of each of theanti-SMNd2 and anti-SMN Kryptate in reconstitution buffer). To provide acontrol signal, three (3) wells in the plate contain only RIPA LysisBuffer and, thus, serve as Blank control wells. The plate is centrifugedfor 1 minute to bring the solution to the bottom of the wells and thenincubated overnight at room temperature. Fluorescence for each well ofthe plate at 665 nm and 620 nm is measured on an EnVision multilabelplate reader (Perkin-Elmer). The total protein in the tissue homogenateis measured using the BCA assay according to the manufacturer'sprotocol.

The normalized fluorescence signal is calculated for each sample, Blankand vehicle control well by dividing the signal at 665 nm by the signalat 620 nm. Normalizing the signal accounts for possible fluorescencequenching due to the matrix effect of the tissue homogenate. The ΔFvalue (a measurement of Smn protein abundance as a percent value) foreach tissue sample well is calculated by subtracting the normalizedaverage fluorescence for the Blank control wells from the normalizedfluorescence for each tissue sample well, then dividing this differenceby the normalized average fluorescence for the Blank control wells andmultiplying the resulting value by 100. The ΔF value for each tissuesample well is divided by the total protein quantity (determined usingthe BCA assay) for that tissue sample. The change in Smn proteinabundance for each tissue sample relative to the vehicle control iscalculated as the percent difference in the ΔF value of the tissuesample in the presence of the test compound and the averaged ΔF value ofthe vehicle control signal divided by the averaged ΔF value of thevehicle control signal.

Example 11 Smn Protein Assay in Tissues of Adult C/C-Allele SMA Mice

The tissues for use in the assay for Smn protein in adult C/C-allele SMAmice are prepared as described in Example 10. The assay assesses whethertreatment of C/C-allele SMA mice with a test compound for 10 daysincreases levels of Smn protein produced from the SMN2 gene.

Materials

Material Source Tissues from C/C-allele The Jackson Laboratory, strainNo.: 008714 SMA mice (B6.129-Smn1^(tm5(Smn1/SMN2)Mrph)/J)

Protocol.

C/C-allele SMA mice are dosed BID orally (in 0.5% hydroxypropylmethylcellulose (HPMC) with 0.1% Tween-80) with a test compound or vehicle at10 mg/kg for 10 days. Age-matched heterozygous mice are dosed withvehicle for use as a control. Tissues are collected for analysis ofprotein levels according to Example 10.

Results.

As seen in FIG. 11, total protein-normalized Smn level was increased inbrain, spinal cord, and muscle tissues of adult C/C-allele SMA micetreated at 100 mg/kg BID for 10 days with Compound 6 (FIG. 11a ) ortreated at 10 mg/kg BID for 10 days with Compound 170 (FIG. 11b )relative to the vehicle group.

Example 12 Smn Protein in Tissues of Neonatal Δ7 SMA Mice

The assay for Smn protein in neonatal SMA mice tissues is used todetermine whether treatment with a test compound increases Smn proteinlevels produced from the SMN2 gene.

Materials

Material Source Tissues from The Jackson Laboratory, strain No.: 005025Δ7 SMA mice (FVB.Cg-Tg(SMN2*delta7)4299Ahmb Tg(SMN2)89AhmbSmn1^(tm1Msd)/J)

Protocol.

SMA Δ7 homozygous knockout mice are dosed once a day (QD)intraperitoneally (IP) with a test compound or vehicle (100% DMSO) frompostnatal day (PND) 3 to PND 9. Tissues are collected for analysis ofprotein levels according to Example 10.

Results.

As seen in FIG. 12, total protein normalized Smn level was dosedependently increased in brain, spinal cord, muscle, and skin tissues ofneonatal SMA Δ7 homozygous knockout mice treated with Compound 6 (FIGS.12a, 12b, 12c and 12d , respectively) and in brain, spinal cord, andmuscle of neonatal SMA Δ7 homozygous knockout mice treated with Compound170 (FIGS. 12e, 12f and 12g respectively).

Example 13 Body Weight of Neonatal Δ7 SMA Mice

The change in body weight of neonatal SMA mice is used to determinewhether treatment with a test compound improves body weight.

Materials

Material Source Tissues from The Jackson Laboratory, strain No.: 005025ΔExon7 SMA mice (FVB.Cg-Tg(SMN2*delta7)4299Ahmb Tg(SMN2)89AhmbSmn1^(tm1Msd)/J)

Protocol.

SMA Δ7 homozygous knockout mice are dosed intraperitoneally (IP) withtest compound or vehicle (100% DMSO) QD from PND 3 until the doseregimen is switched to an oral dose BID in 0.5% hydroxypropylmethylcellulose (HPMC) with 0.1% Tween-80 at a dose 3.16-fold higher than thedose used for IP. Body weights of SMA Δ7 mice treated with test compoundor vehicle and age matched heterozygous mice are recorded every day.

Results.

As seen in FIG. 13, body weight of neonatal SMA Δ7 homozygous knockoutmice treated with Compound 6, dosed IP QD from PND 3 to PND 30, thenorally BID from PND 31 until study end (FIG. 13a ) and Compound 170,dosed IP QD from PND 3 to PND 23, then orally BID from PND 24 untilstudy end (FIG. 13b ), improved compared to vehicle treated mice.

Example 14 Righting Reflex in Neonatal Δ7 SMA Mice

The functional change in righting reflex of neonatal SMA mice is used todetermine whether treatment with a test compound improves rightingreflex.

Materials

Material Source Tissues from The Jackson Laboratory, strain No.: 005025ΔExon7 SMA mice (FVB.Cg-Tg(SMN2*delta7)4299Ahmb Tg(SMN2)89AhmbSmn1^(tm1Msd)/J)

Protocol.

SMA Δ7 homozygous knockout mice are dosed intraperitoneally (IP) withtest compound or vehicle (100% DMSO) QD from PND 3 until the doseregimen is switched to an oral dose BID in 0.5% hydroxypropylmethylcellulose (HPMC) with 0.1% Tween-80 at a dose 3.16-fold higher than thedose used for IP. The righting reflex time is measured as the time takenby a mouse to flip over onto its feet after being laid on its back.Righting reflex is measured five times for each mouse (allowing amaximal time of 30 sec for each try) with 5 minutes between eachmeasurement. The righting reflex time for SMA Δ7 homozygous knockoutmice treated with test compound or vehicle and age-matched heterozygousmice is measured on PND 10, 14 and 18 and plotted.

Results.

As seen in FIG. 14, the righting reflex of neonatal SMA Δ7 homozygousknockout mice treated with Compound 6 (FIG. 14a ) and Compound 170 (FIG.14b ) dosed IP QD from PND 3 improved compared to vehicle treated mice.The righting time of the compound treated neonatal SMA Δ7 homozygousknockout mice was similar to that of the age matched heterozygous miceon PND 18.

Example 15 Survival of Neonatal Δ7 SMA Mice

The change in the number of surviving mice over time is used todetermine whether treatment with a test compound improves survival.

Materials

Material Source Tissues from The Jackson Laboratory, strain No.: 005025Δ7 SMA mice (FVB.Cg-Tg(SMN2*delta7)4299Ahmb Tg(SMN2)89AhmbSmn1^(tm1Msd)/J)

Protocol.

SMA Δ7 homozygous knockout mice are dosed intraperitoneally (IP) withtest compound or vehicle (100% DMSO) QD from PND 3 until the doseregimen is switched to an oral dose BID in 0.5% hydroxypropylmethylcellulose (HPMC) with 0.1% Tween-80 at a dose 3.16-fold higher than thedose used for IP and later switched to an oral dose QD in 0.5%hydroxypropylmethyl cellulose (HPMC) with 0.1% Tween-80 at a dose6.32-fold higher than the dose used for IP. The number of surviving micein each group is recorded every day and plotted as a percent of totalnumber of mice. Tissues of SMA Δ7 and age-matched heterozygous mice arecollected for the measurement of Smn protein levels and processed asdetailed in Example 10. The total protein normalized Smn protein levelsmeasured in the tissues are plotted as a percent of those in theage-matched heterozygous mice tissues, with the Smn level inheterozygous mice set to 100 percent. The level of Smn protein in thetest compound treated mice tissue relative to that in heterozygous micetissue is indicated as a percent value above each bar in the graph.

Results.

As seen in FIG. 15, survival of neonatal SMA Δ7 homozygous knockout micetreated with Compound 6 (FIG. 15a ), dosed IP QD from PND 3 to PND 30,then orally BID from PND 31 until study end, and Compound 170 (FIG. 15b), dosed IP QD from PND 3 to PND 23, then orally BID from PND 24 untilstudy end, improved compared to vehicle treated mice. As seen in FIG.16, Smn protein levels in brain, spinal cord, and muscle tissues of SMAΔ7 homozygous knockout mice after treatment with Compound 6 dosed IP 10mg/kg QD from PND 3 to PND 30, then orally 30 mg/kg BID from PND 31 toPND 156 (FIG. 16a ) and Compound 170 dosed IP 3 mg/kg QD from PND 3 toPND 23, then orally 10 mg/kg BID from PND 24 to PND 88, orally 20 mg/kgQD from PND 89 to PND 185 (FIG. 16b ) was measured and plotted relativeto vehicle treated and age-matched heterozygous mice.

Example 16 Human SMN1 Minigene mRNA End-Point Semi-Quantitative RT-PCRSplicing Assay in Cultured Cells

The RT-PCR assay is used to visualize and quantify the levels of thehuman SMN1 minigene full length and Δ7 mRNA in primary cells and celllines expressing the human SMN1 minigene construct treated with a testcompound.

Materials

Material Source HEK293H cells ATCC Catalog No.: CRL-1573 Cells-To-Ctlysis buffer Life Technologies, Inc. (formerly Applied Biosystems)Catalog No.: 4399002 FuGENE-6 lipid transfection Roche Applied Science,Catalog reagent No.: 11 814 443 001 DMEM Life Technologies, Inc.(formerly Invitrogen) Catalog No.: 11960-044 96-well flat-bottom platesBecton Dickinson Catalog No.: 353072 Platinum Taq HiFi DNA LifeTechnologies, Inc. (formerly Polymerase Super Mix Invitrogen) CatalogNo.: 11304-016 iScript RT enzyme Kit BioRad Catalog No.: 170-8890Ethidium bromide 2% agarose Life Technologies, Inc. (formerly E gels48-Well Double Comb Invitrogen) Catalog No.: G8008-02 Gel DocumentationSystem UVP Gel Doc It 310 Imaging system

SMN1 Minigene Construct

Preparation of the Minigene Constructs

Using the procedure for the preparation of the SMN2 minigene constructdescribed in Biological Example 1, the SMN1 version of the minigene isgenerated by replacing the sixth nucleotide of exon 7 (a thymineresidue) of the SMN2-A minigene construct to cytosine usingsite-directed mutagenesis. Thus, similar to the SMN2-A minigeneconstruct, the SMN1 minigene construct has a single adenine residueinserted after nucleic residue 48 of exon 7. The SMN1 minigene constructis referred to as SMN1-A.

Protocol.

HEK293H cells (10,000 cells/well/199 μL) were transfected, usingFuGENE-6 reagent, in a 96-well plate with 15 ng of the SMN1-A minigenereporter plasmid per well. Cells were incubated for 24 hours followingtransfection. Test compounds were serially diluted 3.16-fold in 100%DMSO to generate a 7-point concentration curve. A solution of testcompound (1 μL, 200× in DMSO) was added to each test well. 1 μL DMSO wasadded to each control well. The plate was incubated for 7 hours in acell culture incubator (37° C., 5% CO₂, 100% relative humidity). Thecells were then lysed in Cells-To-Ct lysis buffer and the lysates werestored at −80° C.

Two SMN spliced mRNA are generated from the SMN1 minigene. The term“SMN1 minigene FL” refers to the first spliced product containing exon7, corresponding to full length SMN1 mRNA. The term “SMN1 minigene Δ7”refers to the second product lacking exon 7.

SMN minigene FL and Δ7 mRNA are amplified using the primers in Table 11.Primer SMN Forward C (SEQ ID NO. 11) hybridizes to a nucleotide sequencein exon 6 (nucleotide 43 to nucleotide 63), primer SMN Reverse A (SEQ IDNO. 2) hybridizes to a nucleotide sequence in the coding sequence ofFirefly luciferase. The combination of these two oligonucleotidesdetects only SMN1 or SMN2 minigenes (RT-PCR) and will not detectendogenous SMN1 or SMN2 genes. Since the HEK293H cells used in Example16 were transfected with only the human SMN1 minigene, RT-PCR canvisualize and quantify only SMN1 minigene full-length and SMN1 minigeneΔ7 mRNA.

TABLE 11 Primer Sequence Source SMN Forward CSEQ ID NO. 11: GATGCTGATGCTTTGGGAAGT PTC¹ SMN Reverse ASEQ ID NO. 2: CGCTTCACATTCCAGATCTGTC PTC¹ ¹Primers designed by PTCTherapeutics, Inc.

To synthesize cDNA, 5 μL of lysate, 4 μL of 5× iScript reaction mix, 1μL of reverse transcriptase, and 10 μL of water are combined andincubated 5 min at 25° C. followed by 30 min at 42° C., followed by 5min at 85° C. The cDNA solution is stored at −20° C.

To perform endpoint PCR, 5 μL of cDNA, 0.2 μL of 100 μM forward primer,0.2 μL of 100 μM reverse primer, and 22.5 μL of polymerase super mix arecombined in a 96 well semiskirted PCR plate. PCR is carried out at thefollowing temperatures for the indicated time: Step 1: 94° C. (2 min),Step 2: 94° C. (30 sec), Step 3: 55° C. (30 sec), Step 4: 68° C. (1min), then repeat Steps 2 to 4 for a total of 33 cycles, then hold at 4°C.

10 μL of each PCR sample is electrophoretically separated on a 2%agarose E-gel for 14 minutes stained with dsDNA staining reagents (e.g.,ethidium bromide) and visualized using a gel imager.

Results.

As seen in FIG. 17, cells treated with increasing concentrations ofCompound 6 (FIG. 17a ) and Compound 170 (FIG. 17b ) containprogressively more SMN1 minigene FL mRNA and less SMN1 minigene Δ7 mRNA,indicating a correction of SMN1 alternative splicing.

Without regard to whether a document cited herein was specifically andindividually indicated as being incorporated by reference, all documentsreferred to herein are incorporated by reference into the presentapplication for any and all purposes to the same extent as if eachindividual reference was fully set forth herein.

Although certain embodiments have been described in detail above, thosehaving ordinary skill in the art will clearly understand that manymodifications are possible in the embodiments without departing from theteachings thereof. All such modifications are intended to be encompassedwithin the claims as described herein.

1-10. (canceled)
 11. A method for enhancing the inclusion of exon 7 ofSMN2 into mRNA that is transcribed from the SMN2 gene, comprisingcontacting a human cell with a compound of Formula (I):

or a form thereof, wherein: w₁ and w₅ are independently C—R_(a) or N; w₂is C—R_(b) or N; w₃, w₄ and w₇ are independently C—R₁, C—R₂, C—R_(a) orN; w₆ is C—R₁, C—R₂, C—R_(c) or N; wherein one of w₃, w₄, w₆ and w₇ isC—R₁ and one other of w₃, w₄, w₆ and w₇ is C—R₂, provided that, when w₃is C—R₁, then w₆ is C—R₂ and w₄ and w₇ are independently C—R_(a) or N;or, when w₃ is C—R₂, then w₆ is C—R₁ and w₄ and w₇ are independentlyC—R_(a) or N; or, when w₄ is C—R₁, then w₇ is C—R₂ and w₃ is C—R_(a) orN and w₆ is C—R_(c) or N: or, when w₄ is C—R₂, then w₇ is C—R₁ and w₃ isC—R_(a) or N and w₆ is C—R_(c) or N; and, wherein any one, two or threeof w₁, w₂, w₃, w₄, w₅, w₆ and w₇ may optionally be N; R₁ is C₁₋₈alkyl,amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino, C₁₋₈alkoxy-C₁₋₈alkyl-amino,(C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino, (C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino,amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl,(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl, C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkyl,(C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,(C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, amino-C₁₋₈alkyl-amino,(amino-C₁₋₈alkyl)₂-amino, (amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,C₁₋₈alkyl-amino-C₁₋₈alkyl-amino, (C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,(C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,[(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino, amino-C₁₋₈alkoxy,C₁₋₈alkyl-amino-C₁₋₈alkoxy, (C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,(C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkoxy, amino-C₂₋₈alkenyl,C₁₋₈alkyl-amino-C₂₋₈alkenyl, (C₁₋₈alkyl)₂-amino-C₂₋₈alkenyl,amino-C₂₋₈alkynyl, C₁₋₈alkyl-amino-C₂₋₈alkynyl,(C₁₋₈alkyl)₂-amino-C₂₋₈alkynyl, halo-C₁₋₈alkyl-amino,(halo-C₁₋₈alkyl)₂-amino, (halo-C₁₋₈alkyl)(C₁₋₈alkyl)amino,hydroxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkoxy-C₁₋₈alkyl,hydroxy-C₁₋₈alkyl-amino, (hydroxy-C₁₋₈alkyl)₂-amino,(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino, hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl,(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl,hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkoxy,hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl-amino,(hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,(hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl-amino,[(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,[(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,heterocyclyl, heterocyclyl-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkoxy,heterocyclyl-amino, (heterocyclyl)(C₁₋₈alkyl)amino,heterocyclyl-amino-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkyl-amino,(heterocyclyl-C₁₋₈alkyl)₂-amino,(heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,heterocyclyl-C₁₋₈alkyl-amino-C₁₋₈alkyl,(heterocyclyl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,(heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, heterocyclyl-oxy,heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C₃₋₁₄cycloalkyl,aryl-C₁₋₈alkyl-amino, (aryl-C₁₋₈alkyl)₂-amino,(aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino, aryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,(aryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,(aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, heteroaryl,heteroaryl-C₁₋₈alkyl, heteroaryl-C₁₋₈alkoxy, heteroaryl-amino,heteroaryl-C₁₋₈alkyl-amino, (heteroaryl-C₁₋₈alkyl)₂-amino,(heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,heteroaryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,(heteroaryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl or(heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl; wherein, each instanceof heterocyclyl, C₃₋₁₄cycloalkyl, aryl and heteroaryl is optionallysubstituted with one, two or three R₃ substituents and optionally, withone additional R₄ substituent; or, wherein, each instance ofheterocyclyl, C₃₋₁₄cycloalkyl, aryl and heteroaryl is optionallysubstituted with one, two, three or four R₃ substituents; R₂ is aryl,aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl orheteroaryl-amino; wherein, each instance of aryl, heterocyclyl andheteroaryl is optionally substituted with one, two or three R₆substituents and optionally, with one additional R₇ substituent; R_(a)is, in each instance, independently selected from hydrogen, halogen orC₁₋₈alkyl; R_(b) is hydrogen, halogen, C₁₋₈alkyl or C₁₋₈alkoxy; R_(c) ishydrogen, halogen or C₁₋₈alkyl; R₃ is, in each instance, independentlyselected from cyano, halogen, hydroxy, oxo, C₁₋₈alkyl, halo-C₁₋₈alkyl,C₁₋₈alkyl-carbonyl, C₁₋₈alkoxy, halo-C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl,C₁₋₈alkoxy-carbonyl, amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino,amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl,(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl, amino-C₁₋₈alkyl-amino,C₁₋₈alkyl-amino-C₁₋₈alkyl-amino, (C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,[(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl]2-amino,(C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,[(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,C₁₋₈alkoxy-C₁₋₈alkyl-amino, (C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino,(C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino, C₁₋₈alkyl-carbonyl-amino,C₁₋₈alkoxy-carbonyl-amino, hydroxy-C₁₋₈alkyl,hydroxy-C₁₋₈alkoxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkyl-amino,(hydroxy-C₁₋₈alkyl)₂-amino or (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino; R₄ isC₃₋₁₄cycloalkyl, C₃₋₁₄cycloalkyl-C₁₋₈alkyl, C₃₋₁₄cycloalkyl-amino,aryl-C₁₋₈alkyl, aryl-C₁₋₈alkoxy-carbonyl, aryl-sulfonyloxy-C₁₋₈alkyl,heterocyclyl or heterocyclyl-C₁₋₈alkyl; wherein, each instance ofC₃₋₁₄cycloalkyl, aryl and heterocyclyl is optionally substituted withone, two or three R₅ substituents; R₅ is, in each instance,independently selected from halogen, hydroxy, cyano, nitro, C₁₋₈alkyl,halo-C₁₋₈alkyl, C₁₋₈alkoxy, halo-C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino,(C₁₋₈alkyl)₂-amino or C₁₋₈alkyl-thio; R₆ is, in each instance,independently selected from halogen, hydroxy, cyano, nitro, C₁₋₈alkyl,C₂₋₈alkenyl, halo-C₁₋₈alkyl, hydroxy-C₁₋₈alkyl, C₁₋₈alkoxy,halo-C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl, amino, C₁₋₈alkyl-amino,(C₁₋₈alkyl)₂-amino or C₁₋₈alkyl-thio; and, R₇ is C₃₋₁₄cycloalkyl,C₃₋₁₄cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl.
 12. A method forincreasing the amount of Smn protein, comprising contacting a human cellwith a compound of Formula (I):

or a form thereof, wherein: w₁ and w₅ are independently C—R_(a) or N; w₂is C—R_(b) or N; w₃, w₄ and w₇ are independently C—R₁, C—R₂, C—R_(a) orN; w₆ is C—R₁, C—R₂, C—R_(c) or N; wherein one of w₃, w₄, w₆ and w₇ isC—R₁ and one other of w₃, w₄, w₆ and w₇ is C—R₂, provided that, when w₃is C—R₁, then w₆ is C—R₂ and w₄ and w₇ are independently C—R_(a) or N;or, when w₃ is C—R₂, then w₆ is C—R₁ and w₄ and w₇ are independentlyC—R_(a) or N; or, when w₄ is C—R₁, then w₇ is C—R₂ and w₃ is C—R_(a) orN and w₆ is C—R_(c) or N: or, when w₄ is C—R₂, then w₇ is C—R₁ and w₃ isC—R_(a) or N and w₆ is C—R_(c) or N; and, wherein any one, two or threeof w₁, w₂, w₃, w₄, w₅, w₆ and w₇ may optionally be N, R₁ is C₁₋₈alkyl,amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino, C₁₋₈alkoxy-C₁₋₈alkyl-amino,(C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino, (C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino,amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl,(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl, C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkyl,(C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,(C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, amino-C₁₋₈alkyl-amino,(amino-C₁₋₈alkyl)₂-amino, (amino-C₁₋₈alkyl)(C₁₋₈alkyl)aminoC₁₋₈alkyl-amino-C₁₋₈alkyl-amino, (C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino(C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,[(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino, amino-C₁₋₈alkoxy,C₁₋₈alkyl-amino-C₁₋₈alkoxy, (C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,(C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkoxy, amino-C₂₋₈alkenyl,C₁₋₈alkyl-amino-C₂₋₈alkenyl, (C₁₋₈alkyl)₂-amino-C₂₋₈alkenyl,amino-C₂₋₈alkynyl, C₁₋₈alkyl-amino-C₂₋₈alkynyl,(C₁₋₈alkyl)₂-amino-C₂₋₈alkynyl, halo-C₁₋₈alkyl-amino,(halo-C₁₋₈alkyl)₂-amino, (halo-C₁₋₈alkyl)(C₁₋₈alkyl)amino,hydroxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkoxy-C₁₋₈alkyl,hydroxy-C₁₋₈alkyl-amino, (hydroxy-C₁₋₈alkyl)₂-amino,(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino, hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl,(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl,hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkoxy,hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl-amino,(hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,(hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl-amino,[(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,[(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,heterocyclyl, heterocyclyl-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkoxy,heterocyclyl-amino, (heterocyclyl)(C₁₋₈alkyl)amino,heterocyclyl-amino-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkyl-amino,(heterocyclyl-C₁₋₈alkyl)₂-amino,(heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,heterocyclyl-C₁₋₈alkyl-amino-C₁₋₈alkyl,(heterocyclyl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,(heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, heterocyclyl-oxy,heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C₃₋₁₄cycloalkyl,aryl-C₁₋₈alkyl-amino, (aryl-C₁₋₈alkyl)₂-amino,(aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino, aryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,(aryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,(aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, heteroaryl,heteroaryl-C₁₋₈alkyl, heteroaryl-C₁₋₈alkoxy, heteroaryl-amino,heteroaryl-C₁₋₈alkyl-amino, (heteroaryl-C₁₋₈alkyl)₂-amino,(heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,heteroaryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,(heteroaryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl or(heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl; wherein, each instanceof heterocyclyl, C₃₋₁₄cycloalkyl, aryl and heteroaryl is optionallysubstituted with one, two or three R₃ substituents and optionally, withone additional R₄ substituent; or, wherein, each instance ofheterocyclyl, C₃₋₁₄cycloalkyl, aryl and heteroaryl is optionallysubstituted with one, two, three or four R₃ substituents; R₂ is aryl,aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl orheteroaryl-amino; wherein, each instance of aryl, heterocyclyl andheteroaryl is optionally substituted with one, two or three R₆substituents and optionally, with one additional R₇ substituent; R_(a)is, in each instance, independently selected from hydrogen, halogen orC₁₋₈alkyl; R_(b) is hydrogen, halogen, C₁₋₈alkyl or C₁₋₈alkoxy; R_(c) ishydrogen, halogen or C₁₋₈alkyl; R₃ is, in each instance, independentlyselected from cyano, halogen, hydroxy, oxo, C₁₋₈alkyl, halo-C₁₋₈alkyl,C₁₋₈alkyl-carbonyl, C₁₋₈alkoxy, halo-C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl,C₁₋₈alkoxy-carbonyl, amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino,amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl,(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl, amino-C₁₋₈alkyl-amino,C₁₋₈alkyl-amino-C₁₋₈alkyl-amino, (C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,[(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl]2-amino,(C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,[(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,C₁₋₈alkoxy-C₁₋₈alkyl-amino, (C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino,(C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino, C₁₋₈alkyl-carbonyl-amino,C₁₋₈alkoxy-carbonyl-amino, hydroxy-C₁₋₈alkyl,hydroxy-C₁₋₈alkoxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkyl-amino,(hydroxy-C₁₋₈alkyl)₂-amino or (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino; R₄ isC₃₋₁₄cycloalkyl, C₃₋₁₄cycloalkyl-C₁₋₈alkyl, C₃₋₁₄cycloalkyl-amino,aryl-C₁₋₈alkyl, aryl-C₁₋₈alkoxy-carbonyl, aryl-sulfonyloxy-C₁₋₈alkyl,heterocyclyl or heterocyclyl-C₁₋₈alkyl; wherein, each instance ofC₃₋₁₄cycloalkyl, aryl and heterocyclyl is optionally substituted withone, two or three R₅ substituents; R₅ is, in each instance,independently selected from halogen, hydroxy, cyano, nitro, C₁₋₈alkyl,halo-C₁₋₈alkyl, C₁₋₈alkoxy, halo-C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino,(C₁₋₈alkyl)₂-amino or C₁₋₈alkyl-thio; R₆ is, in each instance,independently selected from halogen, hydroxy, cyano, nitro, C₁₋₈alkyl,C₂₋₈alkenyl, halo-C₁₋₈alkyl, hydroxy-C₁₋₈alkyl, C₁₋₈alkoxy,halo-C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl, amino, C₁₋₈alkyl-amino,(C₁₋₈alkyl)₂-amino or C₁₋₈alkyl-thio; and, R₇ is C₃₋₁₄cycloalkyl,C₃₋₁₄cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl.
 13. (canceled)14. (canceled)
 15. A method for treating spinal muscular atrophy in ahuman subject in need thereof, comprising administering to the subject apharmaceutical composition comprising an effective amount of a compoundof Formula (I) and a pharmaceutically acceptable carrier, excipient ordiluent:

or a form thereof, wherein: w₁ and w₅ are independently C—R_(a) or N; w₂is C—R_(b) or N; w₃, w₄ and w₇ are independently C—R₁, C—R₂, C—R_(a) orN; w₆ is C—R₁, C—R₂, C—R_(c) or N; wherein one of w₃, w₄, w₆ and w₇ isC—R₁ and one other of w₃, w₄, w₆ and w₇ is C—R₂, provided that, when w₃is C—R₁, then w₆ is C—R₂ and w₄ and w₇ are independently C—R_(a) or N;or, when w₃ is C—R₂, then w₆ is C—R₁ and w₄ and w₇ are independentlyC—R_(a) or N; or, when w₄ is C—R₁, then w₇ is C—R₂ and w₃ is C—R_(a) orN and w₆ is C—R_(c) or N: or, when w₄ is C—R₂, then w₇ is C—R₁ and w₃ isC—R_(a) or N and w₆ is C—R_(c) or N; and, wherein any one, two or threeof w₁, w₂, w₃, w₄, w₅, w₆ and w₇ may optionally be N; R₁ is C₁₋₈alkyl,amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino, C₁₋₈alkoxy-C₁₋₈alkyl-amino,(C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino, (C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino,amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl,(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl, C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkyl,(C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,(C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, amino-C₁₋₈alkyl-amino,(amino-C₁₋₈alkyl)₂-amino, (amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,C₁₋₈alkyl-amino-C₁₋₈alkyl-amino, (C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,(C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,[(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino, amino-C₁₋₈alkoxy,C₁₋₈alkyl-amino-C₁₋₈alkoxy, (C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,(C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkoxy, amino-C₂₋₈alkenyl,C₁₋₈alkyl-amino-C₂₋₈alkenyl, (C₁₋₈alkyl)₂-amino-C₂₋₈alkenyl,amino-C₂₋₈alkynyl, C₁₋₈alkyl-amino-C₂₋₈alkynyl,(C₁₋₈alkyl)₂-amino-C₂₋₈alkynyl, halo-C₁₋₈alkyl-amino,(halo-C₁₋₈alkyl)₂-amino, (halo-C₁₋₈alkyl)(C₁₋₈alkyl)amino,hydroxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkoxy-C₁₋₈alkyl,hydroxy-C₁₋₈alkyl-amino, (hydroxy-C₁₋₈alkyl)₂-amino,(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino, hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl,(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl,hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkoxy,hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl-amino,(hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,(hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl-amino,[(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,[(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,heterocyclyl, heterocyclyl-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkoxy,heterocyclyl-amino, (heterocyclyl)(C₁₋₈alkyl)amino,heterocyclyl-amino-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkyl-amino,(heterocyclyl-C₁₋₈alkyl)₂-amino,(heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,heterocyclyl-C₁₋₈alkyl-amino-C₁₋₈alkyl,(heterocyclyl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,(heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, heterocyclyl-oxy,heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C₃₋₁₄cycloalkyl,aryl-C₁₋₈alkyl-amino, (aryl-C₁₋₈alkyl)₂-amino,(aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino, aryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,(aryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,(aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, heteroaryl,heteroaryl-C₁₋₈alkyl, heteroaryl-C₁₋₈alkoxy, heteroaryl-amino,heteroaryl-C₁₋₈alkyl-amino, (heteroaryl-C₁₋₈alkyl)₂-amino,(heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,heteroaryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,(heteroaryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl or(heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl; wherein, each instanceof heterocyclyl, C₃₋₁₄cycloalkyl, aryl and heteroaryl is optionallysubstituted with one, two or three R₃ substituents and optionally, withone additional R₄ substituent; or, wherein, each instance ofheterocyclyl, C₃₋₁₄cycloalkyl, aryl and heteroaryl is optionallysubstituted with one, two, three or four R₃ substituents; R₂ is aryl,aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl orheteroaryl-amino; wherein, each instance of aryl, heterocyclyl andheteroaryl is optionally substituted with one, two or three R₆substituents and optionally, with one additional R₇ substituent; R_(a)is, in each instance, independently selected from hydrogen, halogen orC₁₋₈alkyl; R_(b) is hydrogen, halogen, C₁₋₈alkyl or C₁₋₈alkoxy; R_(c) ishydrogen, halogen or C₁₋₈alkyl; R₃ is, in each instance, independentlyselected from cyano, halogen, hydroxy, oxo, C₁₋₈alkyl, halo-C₁₋₈alkyl,C₁₋₈alkyl-carbonyl, C₁₋₈alkoxy, halo-C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl,C₁₋₈alkoxy-carbonyl, amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino,amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl,(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl, amino-C₁₋₈alkyl-amino,C₁₋₈alkyl-amino-C₁₋₈alkyl-amino, (C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,[(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl]2-amino,(C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,[(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,C₁₋₈alkoxy-C₁₋₈alkyl-amino, (C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino,(C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino, C₁₋₈alkyl-carbonyl-amino,C₁₋₈alkoxy-carbonyl-amino, hydroxy-C₁₋₈alkyl,hydroxy-C₁₋₈alkoxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkyl-amino,(hydroxy-C₁₋₈alkyl)₂-amino or (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino; R₄ isC₃₋₁₄cycloalkyl, C₃₋₁₄cycloalkyl-C₁₋₈alkyl, C₃₋₁₄cycloalkyl-amino,aryl-C₁₋₈alkyl, aryl-C₁₋₈alkoxy-carbonyl, aryl-sulfonyloxy-C₁₋₈alkyl,heterocyclyl or heterocyclyl-C₁₋₈alkyl; wherein, each instance ofC₃₋₁₄cycloalkyl, aryl and heterocyclyl is optionally substituted withone, two or three R₅ substituents; R₅ is, in each instance,independently selected from halogen, hydroxy, cyano, nitro, C₁₋₈alkyl,halo-C₁₋₈alkyl, C₁₋₈alkoxy, halo-C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino,(C₁₋₈alkyl)₂-amino or C₁₋₈alkyl-thio; R₆ is, in each instance,independently selected from halogen, hydroxy, cyano, nitro, C₁₋₈alkyl,C₂₋₈alkenyl, halo-C₁₋₈alkyl, hydroxy-C₁₋₈alkyl, C₁₋₈alkoxy,halo-C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl, amino, C₁₋₈alkyl-amino,(C₁₋₈alkyl)₂-amino or C₁₋₈alkyl-thio; and, R₇ is C₃₋₁₄cycloalkyl,C₃₋₁₄cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl.
 16. A method fortreating spinal muscular atrophy in a human subject in need thereof,comprising administering to the subject an effective amount of acompound of Formula (IIa1):

or a free acid, free base, salt, isotopologue, stereoisomer, racemate,enantiomer, diastereomer or tautomer thereof, wherein: R₁ isheterocyclyl; wherein, heterocyclyl is optionally substituted with one,two or three R₃ substituents and optionally, with one additional R₄substituent; or, wherein, heterocyclyl is optionally substituted withone, two, three or four R₃ substituents; R₂ is phenyl; wherein, R₂ isoptionally substituted with one, two or three R₆ substituents andoptionally, with one additional R₇ substituent; R_(a) is, in eachinstance, independently selected from hydrogen, halogen or C₁₋₈alkyl;R_(b) is hydrogen, halogen, C₁₋₈alkyl or C₁₋₈alkoxy; R_(c) is hydrogen,halogen or C₁₋₈alkyl; R₃ is, in each instance, independently selectedfrom cyano, halogen, hydroxy, oxo, C₁₋₈alkyl, halo-C₁₋₈alkyl,C₁₋₈alkyl-carbonyl, C₁₋₈alkoxy, halo-C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl,C₁₋₈alkoxy-carbonyl, amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino,amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl,(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl, amino-C₁₋₈alkyl-amino,C₁₋₈alkyl-amino-C₁₋₈alkyl-amino, (C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,[(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl]₂-amino,(C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,[(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,C₁₋₈alkoxy-C₁₋₈alkyl-amino, (C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino,(C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino, C₁₋₈alkyl-carbonyl-amino,C₁₋₈alkoxy-carbonyl-amino, hydroxy-C₁₋₈alkyl,hydroxy-C₁₋₈alkoxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkyl-amino,(hydroxy-C₁₋₈alkyl)₂-amino or (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino; R₄ isC₃₋₁₄cycloalkyl, C₃₋₁₄cycloalkyl-C₁₋₈alkyl, C₃₋₁₄cycloalkyl-amino,aryl-C₁₋₈alkyl, aryl-C₁₋₈alkoxy-carbonyl, aryl-sulfonyloxy-C₁₋₈alkyl,heterocyclyl or heterocyclyl-C₁₋₈alkyl; wherein, each instance ofC₃₋₁₄cycloalkyl, aryl and heterocyclyl is optionally substituted withone, two or three R₅ substituents; R₅ is, in each instance,independently selected from halogen, hydroxy, cyano, nitro, C₁₋₈alkyl,halo-C₁₋₈alkyl, C₁₋₈alkoxy, halo-C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino,(C₁₋₈alkyl)₂-amino or C₁₋₈alkyl-thio; R₆ is, in each instance,independently selected from halogen, hydroxy, cyano, nitro, C₁₋₈alkyl,C₂₋₈alkenyl, halo-C₁₋₈alkyl, hydroxy-C₁₋₈alkyl, C₁₋₈alkoxy,halo-C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl, amino, C₁₋₈alkyl-amino,(C₁₋₈alkyl)₂-amino or C₁₋₈alkyl-thio; and, R₇ is C₃₋₁₄cycloalkyl,C₃₋₁₄cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl.
 17. The method ofclaim 16, wherein R₁ is heterocyclyl selected from azetidinyl,tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl,1,4-diazepanyl, 1,2,5,6-tetrahydropyridinyl,1,2,3,6-tetrahydropyridinyl, hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl,(3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3 aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl,hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl,(3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl,hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl,(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl,octahydro-5H-pyrrolo[3,2-c]pyridinyl,octahydro-6H-pyrrolo[3,4-b]pyridinyl,(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridinyl,(4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridinyl,hexahydropyrrolo[1,2-a]pyrazin-(2H)-one,hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl,(7R,8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl,(8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl,(8aR)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl,(8aS)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl,(8aR)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl,octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[3.1.0]hexyl,(1R,5S)-3-azabicyclo[3.1.0]hexyl, 8-azabicyclo[3.2.1]octyl,(1R,5S)-8-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]oct-2-enyl,(1R,5S)-8-azabicyclo[3.2.1]oct-2-enyl, 9-azabicyclo[3.3.1]nonyl,(1R,5S)-9-azabicyclo[3.3.1]nonyl, 2,5-diazabicyclo[2.2.1]heptyl,(1S,4S)-2,5-diazabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl,3,8-diazabicyclo[3.2.1]octyl, (1R,5S)-3,8-diazabicyclo[3.2.1]octyl,1,4-diazabicyclo[3.2.2]nonyl, azaspiro[3.3]heptyl,2,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[3.5]nonyl,5,8-diazaspiro[3.5]nonyl, 2,7-diazaspiro[4.4]nonyl and6,9-diazaspiro[4.5]decyl; wherein, each instance of heterocyclyl isoptionally substituted one, two or three R₃ substituents and optionally,with one additional R₄ substituent.
 18. The method of claim 16, whereinthe salt is a chloride, hydrobromide, hydrochloride, dihydrochloride,acetate, trifluoroacetate or trifluoroacetic acid salt.
 19. The methodof claim 16, wherein the compound is selected from the group consistingof:2-(4-methoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-methoxyphenyl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-methoxyphenyl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(1,4-diazepan-1-yl)-2-(4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-(3,3-dimethylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-(4-ethylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(1,4-diazepan-1-yl)-2-(3,4-dimethoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-(4-propylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-methoxyphenyl)-7-(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(3,3-dimethylpiperazin-1-yl)-2-(4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3-methoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3-methoxyphenyl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3-methoxyphenyl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(3-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(4-ethylpiperazin-1-yl)-2-(3-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(1,4-diazepan-1-yl)-2-(3-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3-methoxyphenyl)-7-(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-phenyl-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3S)-3-methylpiperazin-1-yl]-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-9-fluoro-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3-chlorophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-chlorophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(piperazin-1-yl)-2-[3-(trifluoromethyl)phenyl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-(piperazin-1-yl)-2-[4-(trifluoromethyl)phenyl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3-methylphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-fluorophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-nitrophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-[4-(dimethylamino)phenyl]-9-fluoro-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-[4-(dimethylamino)phenyl]-9-fluoro-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-fluorophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-[4-(dimethylamino)phenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-[4-(dimethylamino)phenyl]-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethylphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethylphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-[3-(dimethylamino)phenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-[3-(dimethylamino)phenyl]-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-[4-(difluoromethoxy)phenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-[4-(difluoromethoxy)phenyl]-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3-fluorophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3-nitrophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-methylphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-fluoro-4,5-dimethoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-fluoro-4,5-dimethoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-(3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(3,4-dimethoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-[4-methoxy-3-(trifluoromethyl)phenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-[4-methoxy-3-(trifluoromethyl)phenyl]-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-[4-methoxy-3-(trifluoromethyl)phenyl]-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-9-methoxy-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,5-difluoro-4-hydroxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3-fluoro-4-methoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,4-[4-oxo-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-2-yl]benzonitrile2-[3-fluoro-5-(trifluoromethyl)phenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-[4-fluoro-3-(trifluoromethyl)phenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-[2-methoxy-3-(trifluoromethyl)phenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,5-difluorophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(piperazin-1-yl)-2-[3-(trifluoromethoxy)phenyl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-[4-methoxy-3-(trifluoromethoxy)phenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-[4-hydroxy-3-(trifluoromethoxy)phenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-[4-methoxy-3-(trifluoromethoxy)phenyl]-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-[4-hydroxy-3-(trifluoromethoxy)phenyl]-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3-fluoro-4-methoxyphenyl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3-fluoro-4-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2,4-dimethoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2,4-dimethoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-[3-(difluoromethoxy)-4-methoxyphenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-[3-(difluoromethoxy)-4-hydroxyphenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-[3-(difluoromethoxy)-4-methoxyphenyl]-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-[3-(difluoromethoxy)-4-hydroxyphenyl]-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,5-difluorophenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3-chloro-4-methoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3-chloro-4-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3-ethoxy-4-methoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3-ethoxy-4-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-(4-aminopiperidin-1-yl)-2-(3,4-dimethoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3-fluoro-5-methoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3-fluoro-5-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-9-methyl-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3-fluoro-4,5-dimethoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-(4-hydroxypiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-[4-(dimethylamino)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-methoxy-3-methylphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,3-[4-oxo-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-2-yl]benzonitrile2-methoxy-5-[4-oxo-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-2-yl]benzonitrile2-(3-fluoro-4-hydroxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethoxy-3-fluorophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-[3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3-fluoro-4-methylphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3-fluoro-4-methylphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3S)-3-aminopyrrolidin-1-yl]-2-(3,4-dimethoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-9-methyl-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-[(3S)-3-(propan-2-ylamino)pyrrolidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3-fluoro-4-methoxyphenyl)-7-(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-methoxy-3-nitrophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-[3-fluoro-4-(methylsulfanyl)phenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,5-difluoro-4-methoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,5-difluoro-4-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-[4-(dimethylamino)piperidin-1-yl]-2-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3-fluoro-4-methoxyphenyl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3-chloro-5-fluorophenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3-chloro-5-fluorophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3-fluoro-4-methoxyphenyl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-2-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R,4R)-3-(dimethylamino)-4-hydroxypyrrolidin-1-yl]-2-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(4-aminopiperidin-1-yl)-2-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3-fluoro-4-methoxyphenyl)-7-[4-(methylamino)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3-fluoro-4-methoxyphenyl)-7-[(3 aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3-fluoro-4-methoxyphenyl)-7-[(3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-[1-(2-hydroxyethyl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-fluoro-3-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-fluoro-3-methoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-difluoro-5-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-difluoro-5-methoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3-fluoro-4-methoxyphenyl)-7-[(3S)-3-(methylamino)pyrrolidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3-fluoro-4-methoxyphenyl)-7-{4-[(methylamino)methyl]piperidin-1-yl}-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3S)-3-aminopyrrolidin-1-yl]-2-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-{4-[(dimethylamino)methyl]piperidin-1-yl}-2-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one,3-fluoro-5-{7-[(3S)-3-methylpiperazin-1-yl]-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl}benzonitrile3-fluoro-5-[4-oxo-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-2-yl]benzonitrile2-(3-fluoro-4-methoxyphenyl)-7-[(3'S,4'S)-4′-hydroxy-1,3′-bipyrrolidin-1′-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-(1,4-diazepan-1-yl)-2-(3,4-dimethoxyphenyl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3-fluoro-4-methoxyphenyl)-7-[(3aR,6aR)-1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-9-methyl-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-[1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyridin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-9-methyl-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-9-methyl-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-9-methyl-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-9-methyl-7-[(3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-[4-(dimethylamino)piperidin-1-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(1R,5S)-8-azabicyclo[3.2.1]oct-2-en-3-yl]-2-(3,4-dimethoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-(1,2,5,6-tetrahydropyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3-fluoro-4-methoxyphenyl)-7-[(3 aR,6aS)-5-(2-hydroxyethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3-fluoro-4-methoxyphenyl)-7-[(3aS,6aS)-1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3-fluoro-4-methoxyphenyl)-7-[(3 aR,6aS)-5-(propan-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-2-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3-fluoro-4-methoxyphenyl)-7-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3aR,6aS)-5-ethylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-2-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3-fluoro-4-methoxyphenyl)-9-methyl-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3-fluoro-4-methoxyphenyl)-7-[(4aR,7aR)-1-methyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-9-methyl-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3-fluoro-4-methoxyphenyl)-9-methyl-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-[(2R)-2-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3-fluoro-4-methoxyphenyl)-9-methyl-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-[4-(dimethylamino)piperidin-1-yl]-2-(3-fluoro-4-methoxyphenyl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3-fluoro-4-methoxyphenyl)-9-methyl-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[4-(cyclopropylamino)piperidin-1-yl]-2-(3,4-dimethoxyphenyl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-[(3R)-3,4-dimethylpiperazin-1-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-9-methyl-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-[4-(dimethylamino)piperidin-1-yl]-9-ethyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-[1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyridin-4-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-9-methyl-7-[4-(methylamino)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-[4-(ethylamino)piperidin-1-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-8-methyl-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-[4-(propan-2-ylamino)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-(1-cyclobutyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(3,4-dimethoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-[1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-9-methyl-7-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(1-cyclobutyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(3,4-dimethoxyphenyl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-9-methyl-7-[1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-9-methyl-7-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-8-methyl-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(1-cyclopropyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(3,4-dimethoxyphenyl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-8-methyl-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrimido[1,2-b]pyridazin-4-one,2-(3,4-dimethoxyphenyl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one,2-(3-fluoro-4-methoxyphenyl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-(1-ethylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-[cis-4-(methylamino)cyclohexyl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-(piperidin-3-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-9-methyl-7-[4-(propylamino)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-9-ethyl-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-9-ethyl-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-9-methyl-7-[4-(propan-2-ylamino)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-9-ethyl-7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-9-methyl-7-[4-(morpholin-4-yl)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-{4-[(2-hydroxyethyl)amino]piperidin-1-yl}-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-9-ethyl-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[4-(diethylamino)piperidin-1-yl]-2-(3,4-dimethoxyphenyl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-9-ethyl-7-(1-ethylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-{4-[(2-hydroxyethyl)(methyl)amino]piperidin-1-yl)}-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-9-ethyl-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-9-ethyl-7-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-{4-[(2-methoxyethyl)amino]piperidin-1-yl)}-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-{4-[(dimethylamino)methyl]piperidin-1-yl)}-4H-pyrido[1,2-a]pyrimidin-4-one,2-(3,4-dimethoxyphenyl)-7-[4-(pyrrolidin-1-ylmethyl)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,and2-(3,4-dimethoxyphenyl)-7-[4-(piperidin-1-ylmethyl)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,or a salt, isotopologue, stereoisomer, racemate, enantiomer,diastereomer or tautomer thereof.
 20. A method for treating spinalmuscular atrophy in a human subject in need thereof, comprisingadministering to the subject an effective amount of a compound ofFormula (IIa1):

or a form thereof, wherein: R₁ is heterocyclyl; wherein, heterocyclyl isoptionally substituted with one, two or three R₃ substituents andoptionally, with one additional R₄ substituent; or, wherein,heterocyclyl is optionally substituted with one, two, three or four R₃substituents; R₂ is heteroaryl; wherein, heteroaryl is optionallysubstituted with one, two or three R₆ substituents and optionally, withone additional R₇ substituent; R_(a) is, in each instance, independentlyselected from hydrogen, halogen or C₁₋₈alkyl; R_(b) is hydrogen,halogen, C₁₋₈alkyl or C₁₋₈alkoxy; R_(c) is hydrogen, halogen orC₁₋₈alkyl; R₃ is, in each instance, independently selected from cyano,halogen, hydroxy, oxo, C₁₋₈alkyl, halo-C₁₋₈alkyl, C₁₋₈alkyl-carbonyl,C₁₋₈alkoxy, halo-C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl, C₁₋₈alkoxy-carbonyl,amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino, amino-C₁₋₈alkyl,C₁₋₈alkyl-amino-C₁₋₈alkyl, (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,amino-C₁₋₈alkyl-amino, C₁₋₈alkyl-amino-C₁₋₈alkyl-amino,(C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino, (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,[(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl]₂-amino,(C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,[(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,C₁₋₈alkoxy-C₁₋₈alkyl-amino, (C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino,(C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino, C₁₋₈alkyl-carbonyl-amino,C₁₋₈alkoxy-carbonyl-amino, hydroxy-C₁₋₈alkyl,hydroxy-C₁₋₈alkoxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkyl-amino,(hydroxy-C₁₋₈alkyl)₂-amino or (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino; R₄ isC₃₋₁₄cycloalkyl, C₃₋₁₄cycloalkyl-C₁₋₈alkyl, C₃₋₁₄cycloalkyl-amino,aryl-C₁₋₈alkyl, aryl-C₁₋₈alkoxy-carbonyl, aryl-sulfonyloxy-C₁₋₈alkyl,heterocyclyl or heterocyclyl-C₁₋₈alkyl; wherein, each instance ofC₃₋₁₄cycloalkyl, aryl and heterocyclyl is optionally substituted withone, two or three R₅ substituents; R₅ is, in each instance,independently selected from halogen, hydroxy, cyano, nitro, C₁₋₈alkyl,halo-C₁₋₈alkyl, C₁₋₈alkoxy, halo-C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino,(C₁₋₈alkyl)₂-amino or C₁₋₈alkyl-thio; R₆ is, in each instance,independently selected from halogen, hydroxy, cyano, nitro, C₁₋₈alkyl,C₂₋₈alkenyl, halo-C₁₋₈alkyl, hydroxy-C₁₋₈alkyl, C₁₋₈alkoxy,halo-C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl, amino, C₁₋₈alkyl-amino,(C₁₋₈alkyl)₂-amino or C₁₋₈alkyl-thio; and, R₇ is C₃₋₁₄cycloalkyl,C₃₋₁₄cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl.
 21. The method ofclaim 20, wherein the compound is selected from the group consisting of:2-(6-methylimidazo[1,2-a]pyridin-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(6-methylimidazo[1,2-a]pyrazin-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(6-methylimidazo[1,2-a]pyrazin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(6-methoxypyridin-3-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(5-fluoropyridin-3-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(5-fluoropyridin-3-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(5-chloropyridin-3-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(5-chloropyridin-3-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(5-chloro-6-methoxypyridin-3-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(1H-indol-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(1H-indol-5-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(imidazo[1,2-a]pyridin-7-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(imidazo[1,2-a]pyridin-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-(1,4-diazepan-1-yl)-2-(2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-(piperazin-1-yl)-2-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-ethylimidazo[1,2-a]pyridin-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2,3-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(1,4-diazepan-1-yl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methyl-1,3-benzoxazol-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methyl-1,3-benzoxazol-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methyl-1,3-benzothiazol-5-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methyl-1,3-benzothiazol-5-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methyl-2H-indazol-5-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methyl-2H-indazol-5-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methyl-1,3-benzoxazol-5-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methyl-1,3-benzoxazol-5-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-(1,4-diazepan-1-yl)-2-(2-methyl-1,3-benzothiazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3S)-3-methylpiperazin-1-yl]-2-(4-methyl-1,3-thiazol-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-methyl-1,3-thiazol-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(4-methyl-1,4-diazepan-1-yl)-2-(2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methyl-1,3-benzoxazol-6-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(5-fluoro-6-methoxypyridin-3-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(5-fluoro-6-methoxypyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(2-methyl-1,3-benzothiazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methyl-1,3-benzothiazol-5-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methyl-1,3-benzothiazol-5-yl)-7-(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2-(2-methyl-1,3-benzothiazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-methyl-1H-imidazol-1-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-methyl-1H-imidazol-1-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(5-fluoro-6-methoxypyridin-3-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3S)-3-methylpiperazin-1-yl]-2-(1-methyl-1H-pyrazol-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(1-methyl-1H-pyrazol-4-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methyl-1,3-benzoxazol-6-yl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-(3,3-dimethylpiperazin-1-yl)-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(1,4-diazepan-1-yl)-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methyl-1,3-benzoxazol-6-yl)-7-(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,5-dimethoxypyridin-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(4-ethylpiperazin-1-yl)-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methyl-1,3-benzothiazol-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methyl-1,3-benzothiazol-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(6-methoxypyridin-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(piperazin-1-yl)-2-(pyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(5-methoxypyridin-3-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3S)-3,4-dimethylpiperazin-1-yl]-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[4-(dimethylamino)piperidin-1-yl]-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(4-aminopiperidin-1-yl)-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R)-3,4-dimethylpiperazin-1-yl]-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(1,4-diazepan-1-yl)-2-(2-methyl-1,3-benzothiazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methyl-1,3-benzothiazol-6-yl)-7-(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2-(2-methyl-1,3-benzothiazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methyl-1,3-benzothiazol-6-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3S)-3,4-dimethylpiperazin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-ethyl-1,3-benzoxazol-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-ethyl-1,3-benzoxazol-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methyl-1,3-benzoxazol-6-yl)-7-[(3 aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-(4-aminopiperidin-1-yl)-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(3,3-dimethylpiperazin-1-yl)-2-(2-methyl-1,3-benzothiazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2-(2-methyl-1,3-benzothiazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[4-(dimethylamino)piperidin-1-yl]-2-(2-methyl-1,3-benzothiazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methyl-1,3-benzothiazol-6-yl)-7-(piperidin-4-yloxy)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3S)-3,4-dimethylpiperazin-1-yl]-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R)-3,4-dimethylpiperazin-1-yl]-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[4-(dimethylamino)piperidin-1-yl]-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methyl-1,3-benzoxazol-6-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methyl-1,3-benzoxazol-6-yl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3S)-3,4-dimethylpiperazin-1-yl]-2-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(4-ethylpiperazin-1-yl)-2-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-7-(4-propylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-7-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-3,4-dimethylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-ethylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[4-(dimethylamino)piperidin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(3,3-dimethylpiperazin-1-yl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(4-cyclopropylpiperazin-1-yl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3R)-4-ethyl-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-[4-(dimethylamino)piperidin-1-yl]-2-(2-methyl-1,3-benzothiazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(4-aminopiperidin-1-yl)-2-(2-methyl-1,3-benzothiazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-2-(2-methyl-1,3-benzothiazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(1-cyclopropyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-(1-cyclobutyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[4-(propan-2-yl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[4-(propan-2-yl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-(4-aminopiperidin-1-yl)-2-(2-methyl-1,3-benzothiazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(3-aminopyrrolidin-1-yl)-2-(2-methyl-1,3-benzothiazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-2-(2-methyl-1,3-benzothiazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methyl-1,3-benzothiazol-6-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[4-(2-methoxyethyl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methyl-1,3-benzothiazol-6-yl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyridin-4-yl]-2-(2-methyl-1,3-benzothiazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methyl-1,3-benzothiazol-6-yl)-7-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-(1-cyclopropyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(2-methyl-1,3-benzothiazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(2-methyl-1,3-benzothiazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R)-3,4-dimethylpiperazin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]hept-2-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-(4-cyclopropylpiperazin-1-yl)-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methyl-1,3-benzothiazol-6-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(pyrrolidin-1-yl)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-(1,4′-bipiperidin-1′-yl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(morpholin-4-yl)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[4-(dimethylamino)piperidin-1-yl]-2-(2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-[4-(pyrrolidin-1-yl)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methyl-1,3-benzothiazol-6-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(4-methylpiperazin-1-yl)-2-(6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3S)-3-methylpiperazin-1-yl]-2-(6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(6-methylpyrazolo[,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(1-methyl-1H-indazol-5-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-[6-(dimethylamino)pyridin-3-yl]-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[4-(diethylamino)piperidin-1-yl]-2-(2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(1-methyl-1H-indazol-5-yl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-[6-(dimethylamino)pyridin-3-yl]-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[4-(diethylamino)piperidin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-ethylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,7-[4-(dimethylamino)piperidin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(1-methyl-1H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(1-methyl-1H-indazol-5-yl)-7-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-[6-(dimethylamino)pyridin-3-yl]-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(4-ethylpiperazin-1-yl)-2-(6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2-(6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[4-(dimethylamino)piperidin-1-yl]-2-(6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[4-(2-hydroxyethyl)piperazin-1-yl]-2-(6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1-propylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyridin-4-yl]-2-(1-methyl-1H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R)-3-methylpiperazin-1-yl]-2-(6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methyl-2H-indazol-5-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(1-methyl-1H-indazol-5-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methyl-2H-indazol-5-yl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(2-methyl-2H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(1-ethylpiperidin-4-yl)-2-(2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]-4H-pyrazino[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,7-(1-cyclopropyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-(6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(1-methyl-1H-indazol-5-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(1-methyl-1H-indazol-5-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[4-(dimethylamino)piperidin-1-yl]-2-(1-methyl-1H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(4-methyl-1,4-diazepan-1-yl)-2-(1-methyl-1H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrimido[1,2-b]pyridazin-4-one,2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(4-ethylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3R)-4-ethyl-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-4-ethyl-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3R)-3-methyl-4-(propan-2-yl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-3-methyl-4-(propan-2-yl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-ethylpiperazin-1-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R)-3,4-dimethylpiperazin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3R)-4-ethyl-3-methylpiperazin-1-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1-ethylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[1-(propan-2-yl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-[4-(dimethylamino)piperidin-1-yl]-2-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-[4-(2-hydroxyethyl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(2-hydroxyethyl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(2-hydroxyethyl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3R)-4-(2-hydroxyethyl)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-4-(2-methoxyethyl)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-{(3S)-4-[2-(2-hydroxyethoxy)ethyl]-3-methylpiperazin-1-yl}-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-4-cyclopropyl-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-4-cyclobutyl-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-4-(2-hydroxyethyl)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-4-(2-methoxyethyl)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-4-(2-hydroxyethyl)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-{(3S)-4-[2-(2-hydroxyethoxy)ethyl]-3-methylpiperazin-1-yl}-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-3-methyl-4-(propan-2-yl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3S)-4-cyclopropyl-3-methylpiperazin-1-yl]-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3S)-4-cyclobutyl-3-methylpiperazin-1-yl]-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(3,3-dimethylpiperazin-1-yl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-(1-methyl-11H-indazol-5-yl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-ethylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(2-hydroxyethyl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-[4-(dimethylamino)piperidin-1-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[4-(diethylamino)piperidin-1-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(1-methyl-1H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(1-methyl-1H-indazol-5-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-[1-(propan-2-yl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methylimidazo[1,2-a]pyridin-7-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methylimidazo[1,2-a]pyridin-7-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methylimidazo[1,2-a]pyridin-7-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(4-ethylpiperazin-1-yl)-2-(2-methylimidazo[1,2-a]pyridin-7-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methylimidazo[1,2-a]pyridin-7-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(1-ethylpiperidin-4-yl)-2-(2-methylimidazo[1,2-a]pyridin-7-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3S)-3,4-dimethylpiperazin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-[(3R,5S)-3,4,5-trimethylpiperazine-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-{4-[(dimethylamino)methyl]piperidin-1-yl}-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(pyrrolidin-1-ylmethyl)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(piperidin-1-ylmethyl)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-[1-(2-hydroxyethyl)piperidin-4-yl]-2-(2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyridin-4-yl]-2-(2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methyl-2H-indazol-5-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-{4-[(2-hydroxyethyl)(methyl)amino]piperidin-1-yl)}-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-[4-(propylamino)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-(4-amino-4-methylpiperidin-1-yl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(ethylamino)piperidin-1-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,7-{4-[bis(2-hydroxyethyl)amino]piperidin-1-yl}-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(oxetan-3-yl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-(4-ethylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-methyloctahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(1-methyl-1H-indazol-5-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(1-ethylpiperidin-4-yl)-2-(1-methyl-1H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[1-(2-hydroxyethyl)piperidin-4-yl]-2-(1-methyl-1H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methyl-2H-indazol-5-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methyl-2H-indazol-5-yl)-7-[1-(propan-2-yl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-{4-[(2-hydroxyethyl)amino]piperidin-1-yl}-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-[4-(methylamino)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-[4-(propan-2-ylamino)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-(1-ethylpiperidin-4-yl)-2-(2-methyl-2H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[1-(2-hydroxyethyl)piperidin-4-yl]-2-(2-methyl-2H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(1-ethylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-[1-(propan-2-yl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-[1-(2-hydroxyethyl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-propylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(propan-2-yl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-(4-cyclopropylpiperazin-1-yl)-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(4-cyclobutylpiperazin-1-yl)-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(oxetan-3-yl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-ethyloctahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(2-hydroxyethyl)octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-methoxy-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-hydroxy-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R)-3,4-dimethylpiperazin-1-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R)-4-ethyl-3-methylpiperazin-1-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3R)-3-methyl-4-propylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3R)-4-(2-hydroxyethyl)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(pyrrolidin-1-yl)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(propan-2-yl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-(1-cyclopropylpiperidin-4-yl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(1-cyclobutylpiperidin-4-yl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3R)-3-methyl-4-(propan-2-yl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R)-4-cyclopropyl-3-methylpiperazin-1-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R)-4-cyclobutyl-3-methylpiperazin-1-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3R)-3-methyl-4-(oxetan-3-yl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[4-(2-hydroxyethyl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-(4-cyclobutylpiperazin-1-yl)-2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3R)-4-(2-hydroxyethyl)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R)-4-cyclobutyl-3-methylpiperazin-1-yl]-2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-4-(2-hydroxyethyl)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3S)-4-cyclobutyl-3-methylpiperazin-1-yl]-2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-ethylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(2-hydroxyethyl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-propylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(2-fluoroethyl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(3-fluoropropyl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(2-fluoroethyl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(3-fluoropropyl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3R)-4-(2-fluoroethyl)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3R)-4-(3-fluoropropyl)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(2-fluoroethyl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(3-fluoropropyl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-{(3R)-4-[2-(2-hydroxyethoxy)ethyl]-3-methylpiperazin-1-yl}-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3R)-4-(2-hydroxyethyl)-3-methylpiperazin-1-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-[8-(hydroxymethyl)-2-methylimidazo[1,2-a]pyridin-6-yl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-[8-(hydroxymethyl)-2-methylimidazo[1,2-a]pyridin-6-yl]-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(4-ethylpiperazin-1-yl)-2-[8-(hydroxymethyl)-2-methylimidazo[1,2-a]pyridin-6-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(propan-2-yl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-(1-cyclopropylpiperidin-4-yl)-2-(4-ethyl-6-methypyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(1-cyclobutylpiperidin-4-yl)-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(oxetan-3-yl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-cyclopropyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-cyclopropyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-cyclopropyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-ethylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-cyclopropyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(2-hydroxyethyl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-propylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-[4-(dimethylamino)-6-methylpyrazolo[1,5-a]pyrazin-2-yl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methyl-1H-benzimidazol-6-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(4-ethylpiperazin-1-yl)-2-(2-methyl-1H-benzimidazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[1-(2,2-dimethyl-1,3-dioxan-5-yl)piperidin-4-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[1-(1,3-dihydroxypropan-2-yl)piperidin-4-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1-ethylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[1-(2-hydroxyethyl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R)-3,4-dimethylpiperazin-1-yl]-2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3R)-4-ethyl-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-ethylpiperidin-4-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(2-hydroxyethyl)piperidin-4-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,7-(1-cyclobutylpiperidin-4-yl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,9-methyl-2-(2-methyl-2H-indazol-5-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[4-(dimethylamino)-4-methylpiperidin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1, 5-a]pyrazin-2-yl)-7-[4-(ethylamino)-4-methylpiperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-methyl-4-(propylamino)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-{4-[(2-hydroxyethyl)amino]-4-methylpiperidin-1-yl}-4H-pyrido[1,2-a]pyrimidin-4-one,7-(1-cyclobutylpiperidin-4-yl)-9-methyl-2-(2-methyl-2H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[1-(2-hydroxyethyl)piperidin-4-yl]-9-methyl-2-(2-methyl-2H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(1-propylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-cyclopropyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-cyclopropyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-cyclopropyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-cyclopropyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-(1-cyclopropylpiperidin-4-yl)-9-methyl-2-(2-methyl-2H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(1-ethylpiperidin-4-yl)-9-methyl-2-(2-methyl-2H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,9-methyl-2-(2-methyl-2H-indazol-5-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(1-methylpiperidin-4-yl)oxy]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(6-methyl-4-propylpyrazolo[1,5-a]pyrazin-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(4-methylpiperazin-1-yl)-2-(6-methyl-4-propylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(4-ethylpiperazin-1-yl)-2-(6-methyl-4-propylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[4-(2-hydroxyethyl)piperazin-1-yl]-2-(6-methyl-4-propylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R)-3-methylpiperazin-1-yl]-2-(6-methyl-4-propylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3S)-3-methylpiperazin-1-yl]-2-(6-methyl-4-propylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(6-methyl-4-propylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-[(3R)-3-methyl-4-(propan-2-yl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-(4-amino-4-methylpiperidin-1-yl)-2-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3S)-3-ethylpiperazin-1-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-[2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R)-3-methylpiperazin-1-yl]-2-[2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3S)-3-methylpiperazin-1-yl]-2-[2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-[2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-(4-amino-4-methylpiperidin-1-yl)-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2,7-dimethyl-2H-indazol-5-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2,7-dimethyl-2H-indazol-5-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2,7-dimethyl-2H-indazol-5-yl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-(3-aminopropyl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(1-ethyl-3-methylpyrrolo[1,2-a]pyrazin-7-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(1,4-diazepan-1-yl)-2-(1-ethyl-3-methylpyrrolo[1,2-a]pyrazin-7-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2,7-dimethyl-2H-indazol-5-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2,7-dimethyl-2H-indazol-5-yl)-7-[(3S)-3,4-dimethylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2,7-dimethyl-2H-indazol-5-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2,7-dimethyl-2H-indazol-5-yl)-7-(1-ethylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,9-methyl-2-(2-methyl-2H-indazol-5-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,9-methyl-2-(2-methyl-2H-indazol-5-yl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,9-methyl-2-(2-methyl-2H-indazol-5-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-[3-(dimethylamino)azetidin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[3-(diethylamino)azetidin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[3-(pyrrolidin-1-yl)azetidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-(1,4-diazepan-1-yl)-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-2-(6-methyl-4-propylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(6-methyl-4-propylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3S)-3-(aminomethyl)pyrrolidin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[3-(piperidin-1-yl)azetidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(6-methyl-4-propylpyrazolo[1,5-a]pyrazin-2-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(2,7-diazaspiro[4.4]non-2-yl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2,7-dimethyl-2H-indazol-5-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-{(3S)-3-[(dimethylamino)methyl]pyrrolidin-1-yl}-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,9-methyl-2-(1-methyl-1H-indazol-5-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(1,7-dimethyl-1H-indazol-5-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(1,7-dimethyl-1H-indazol-5-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(1,7-dimethyl-1H-indazol-5-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-{(3S)-3-[(diethylamino)methyl]pyrrolidin-1-yl}-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-{(3S)-3-[(ethylamino)methyl]pyrrolidin-1-yl}-4H-pyrido[1,2-a]pyrimidin-4-one,7-{3-[(dimethylamino)methyl]azetidin-1-yl}-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-{3-[(diethylamino)methyl]azetidin-1-yl}-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(1-ethyl-3-methylpyrrolo[1,2-a]pyrazin-7-yl)-7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,9-methyl-2-(1-methyl-1H-indazol-5-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R)-3,4-dimethylpiperazin-1-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,7-(1-ethylpiperidin-4-yl)-9-methyl-2-(1-methyl-1H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-[1-(2-hydroxyethyl)piperidin-4-yl]-9-methyl-2-(1-methyl-1H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3S)-3,4-dimethylpiperazin-1-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-ethylpiperidin-4-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,7-(1-cyclobutylpiperidin-4-yl)-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(2-hydroxyethyl)piperidin-4-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R)-3-(aminomethyl)pyrrolidin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(2S,6S)-2,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-{(3R)-3-[(dimethylamino)methyl]pyrrolidin-1-yl}-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(2S,6S)-2,6-dimethylpiperidin-4-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[4-(2-hydroxyethyl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(imidazo[1,2-a]pyridin-6-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-(2,7-diazaspiro[3.5]non-7-yl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(4-methylpiperazin-1-yl)-2-(2-methyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(4-methylpiperazin-1-yl)-2-[2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-methyl-6-[7-(4-methylpiperazin-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl]imidazo[1,2-a]pyridine-8-carbonitrile2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(4,7-diazaspiro[2.5]oct-7-yl)-2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(4-hydroxypiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(8aS)-8a-methylhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-ethylpiperazin-1-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(4-ethylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(8a-methylhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-{[2-(morpholin-4-yl)ethyl]amino}-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,or2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,or a salt, isotopologue, stereoisomer, racemate, enantiomer,diastereomer or tautomer thereof.
 22. The method of claim 20, wherein R₁is heterocyclyl selected from azetidinyl, tetrahydrofuranyl,pyrrolidinyl, piperidinyl, piperazinyl, 1,4-diazepanyl,1,2,5,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl,hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl,(3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl,(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl,hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl,(3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl,hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl,(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl,octahydro-5H-pyrrolo[3,2-c]pyridinyl,octahydro-6H-pyrrolo[3,4-b]pyridinyl,(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridinyl,(4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridinyl,hexahydropyrrolo[1,2-a]pyrazin-(2H)-one,hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl,(7R,8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl,(8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl,(8aR)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl,(8aS)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl,(8aR)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl,octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[3.1.0]hexyl,(1R,5S)-3-azabicyclo[3.1.0]hexyl, 8-azabicyclo[3.2.1]octyl,(1R,5S)-8-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]oct-2-enyl,(1R,5S)-8-azabicyclo[3.2.1]oct-2-enyl, 9-azabicyclo[3.3.1]nonyl,(1R,5S)-9-azabicyclo[3.3.1]nonyl, 2,5-diazabicyclo[2.2.1]heptyl,(1S,4S)-2,5-diazabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl,3,8-diazabicyclo[3.2.1]octyl, (1R,5S)-3,8-diazabicyclo[3.2.1]octyl,1,4-diazabicyclo[3.2.2]nonyl, azaspiro[3.3]heptyl,2,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[3.5]nonyl,5,8-diazaspiro[3.5]nonyl, 2,7-diazaspiro[4.4]nonyl and6,9-diazaspiro[4.5]decyl; wherein, each instance of heterocyclyl isoptionally substituted one, two or three R₃ substituents and optionally,with one additional R₄ substituent.
 23. The method of claim 20, whereinR₂ is heteroaryl selected from furo[3,2-b]pyridinyl,furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, thieno[3,2-c]pyridinyl,thieno[2,3-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl,1H-pyrrolo[2,3-c]pyridinyl, pyrrolo[1,2-a]pyrimidinyl,pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-b]pyridazinyl,pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrazinyl,imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrimidinyl,imidazo[1,2-c]pyrimidinyl, imidazo[1,2-b]pyridazinyl,imidazo[1,2-a]pyrazinyl, imidazo[2,1-b][1,3]thiazolyl,imidazo[2,1-b][1,3,4]thiadiazolyl, [1,3]oxazolo[4,5-b]pyridinyl andquinoxalinyl; wherein, each instance of heteroaryl is optionallysubstituted with one, two or three R₆ substituents and optionally, withone additional R₇ substituent.
 24. The method of claim 20, wherein R₃ isC₁₋₈alkyl selected from methyl, ethyl, propyl, isopropyl and tert-butyl.25. The method of claim 20, wherein R₆ is C₁₋₈alkyl selected frommethyl, ethyl, propyl, isopropyl and tert-butyl.
 26. The method of claim20, wherein R_(a) is, in each instance, hydrogen.
 27. The method ofclaim 20, wherein R_(b) is C₁₋₈alkyl.
 28. The method of claim 20,wherein R_(c) is hydrogen or C₁₋₈alkyl.
 29. The method of claim 20,wherein the form is selected from a free acid, free base, salt,isotopologue, stereoisomer, racemate, enantiomer, diastereomer ortautomer thereof.
 30. The method of claim 29, wherein the salt form is achloride, hydrobromide, hydrochloride, dihydrochloride, acetate,trifluoroacetate or trifluoroacetic acid salt.
 31. The compound of claim21, wherein the compound is selected from the group consisting of:2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-ethylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(propan-2-yl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-ethylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-propylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(propan-2-yl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-propylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(1-propylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(6-methyl-4-propylpyrazolo[1,5-a]pyrazin-2-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-ethylpiperidin-4-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-ethylpiperidin-4-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,or7-[(2S,6S)-2,6-dimethylpiperidin-4-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,or a salt, isotopologue, stereoisomer, racemate, enantiomer,diastereomer or tautomer thereof.
 32. The compound of claim 21, whereinthe compound is selected from the group consisting of:2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3S)-3,4-dimethylpiperazin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-ethylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(3,3-dimethylpiperazin-1-yl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3R)-4-ethyl-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R)-3,4-dimethylpiperazin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(4-methylpiperazin-1-yl)-2-(6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3S)-3-methylpiperazin-1-yl]-2-(6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(4-ethylpiperazin-1-yl)-2-(6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R)-3-methylpiperazin-1-yl]-2-(6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-ethylpiperazin-1-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R)-3,4-dimethylpiperazin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3R)-4-ethyl-3-methylpiperazin-1-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,7-(3,3-dimethylpiperazin-1-yl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-ethylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3S)-3,4-dimethylpiperazin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-propylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(propan-2-yl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R)-3,4-dimethylpiperazin-1-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R)-4-ethyl-3-methylpiperazin-1-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3R)-3-methyl-4-propylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3R)-3-methyl-4-(propan-2-yl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(6-methyl-4-propylpyrazolo[1,5-a]pyrazin-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(4-methylpiperazin-1-yl)-2-(6-methyl-4-propylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(4-ethylpiperazin-1-yl)-2-(6-methyl-4-propylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R)-3-methylpiperazin-1-yl]-2-(6-methyl-4-propylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3S)-3-methylpiperazin-1-yl]-2-(6-methyl-4-propylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(6-methyl-4-propylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3S)-3-ethylpiperazin-1-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R)-3,4-dimethylpiperazin-1-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3S)-3,4-dimethylpiperazin-1-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,or2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-ethylpiperazin-1-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,or a salt, isotopologue, stereoisomer, racemate, enantiomer,diastereomer or tautomer thereof.
 33. The compound of claim 21, whereinthe compound is selected from the group consisting of:2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1-propylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(1-ethylpiperidin-4-yl)-2-(2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-[1-(propan-2-yl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methylimidazo[1,2-a]pyridin-7-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methylimidazo[1,2-a]pyridin-7-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(1-ethylpiperidin-4-yl)-2-(2-methylimidazo[1,2-a]pyridin-7-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(1-ethylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-[1-(propan-2-yl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,or2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1-ethylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,or a salt, isotopologue, stereoisomer, racemate, enantiomer,diastereomer or tautomer thereof.
 34. The compound of claim 21, whereinthe compound is selected from the group consisting of:2-(imidazo[1,2-a]pyridin-7-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(imidazo[1,2-a]pyridin-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methylimidazo[1,2-a]pyridin-7-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2-methylimidazo[1,2-a]pyridin-7-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-(4-ethylpiperazin-1-yl)-2-(2-methylimidazo[1,2-a]pyridin-7-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,7-[(3R)-3,4-dimethylpiperazin-1-yl]-2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3R)-4-ethyl-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(imidazo[1,2-a]pyridin-6-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,or2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(4-ethylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,or a salt, isotopologue, stereoisomer, racemate, enantiomer,diastereomer or tautomer thereof.
 35. The compound of claim 21, whereinthe compound is selected from the group consisting of:2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-ethylpiperidin-4-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(1-propylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(6-methyl-4-propylpyrazolo[1,5-a]pyrazin-2-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,or2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,or a salt, isotopologue, stereoisomer, racemate, enantiomer,diastereomer or tautomer thereof.
 36. The compound of claim 21, whereinthe compound is selected from the group consisting of:2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,or2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(4-ethylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,or a salt, isotopologue, stereoisomer, racemate, enantiomer,diastereomer or tautomer thereof.
 37. The compound of claim 21, whereinthe compound is selected from the group consisting of:2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-ethylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-ethylpiperazin-1-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,or2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-ethylpiperazin-1-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,or a salt, isotopologue, stereoisomer, racemate, enantiomer,diastereomer or tautomer thereof.
 38. The compound of claim 21, whereinthe compound is selected from the group consisting of:2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(1-ethylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-[1-(propan-2-yl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,or2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,or a salt, isotopologue, stereoisomer, racemate, enantiomer,diastereomer or tautomer thereof.